Protein Kinases, catalytic domain; The protein kinase superfamily is mainly composed of the catalytic domains of serine/threonine-specific and tyrosine-specific protein kinases. It also includes RIO kinases, which are atypical serine protein kinases, aminoglycoside phosphotransferases, and choline kinases. These proteins catalyze the transfer of the gamma-phosphoryl group from ATP to hydroxyl groups in specific substrates such as serine, threonine, or tyrosine residues of proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 MEGCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFGKAIRIKDQNGNQ 82
Cdd:cd00180  73 CEGGSLKDLLKENKGPLSEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDG---TVKLADFGLAKDLDSDDSLL 149

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 71988619  83 LPGHQDGIDYsrcsQHSVNVILGIAPTQNDDWSSLVYLLMKMRGF 127
Cdd:cd00180 150 KTTGGTTPPY----YAPPELLGGRYYGPKVDIWSLGVILYELEEL 190

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 MEGCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFGKAIRIKDQNGNQ 82
Cdd:cd00180  73 CEGGSLKDLLKENKGPLSEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDG---TVKLADFGLAKDLDSDDSLL 149

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 71988619  83 LPGHQDGIDYsrcsQHSVNVILGIAPTQNDDWSSLVYLLMKMRGF 127
Cdd:cd00180 150 KTTGGTTPPY----YAPPELLGGRYYGPKVDIWSLGVILYELEEL 190

Serine/Threonine protein kinases, catalytic domain; Phosphotransferases. Serine or threonine-specific kinase subfamily.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 71988619      3 MEGCNLRDIGKQTpGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKAIRIKD 77
Cdd:smart00220  79 CEGGDLFDLLKKR-GRLSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILL---DEDGHVKLADFGLARQLDP 149

serine/threonine-protein kinase PknD;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 71988619   20 SFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVCTLkliDFGKAIRIKDQNGNQL 83
Cdd:PRK13184 111 SVGAFLSIFHKICATIEYVHSKGVLHRDLKPDNILLGLFGEVVIL---DWGAAIFKKLEEEDLL 171

TOMM system kinase/cyclase fusion protein; This model represents proteins of 1350 in length, in multiple species of Burkholderia, in Acidovorax avenae subsp. citrulli AAC00-1 and Delftia acidovorans SPH-1, and in multiple copies in Sorangium cellulosum, in genomic neighborhoods that include a cyclodehydratase/docking scaffold fusion protein (TIGR03882) and a member of the thiazole/oxazole modified metabolite (TOMM) precursor family TIGR03795. It has a kinase domain in the N-terminal 300 amino acids, followed by a cyclase homology domain, followed by regions without named domain definitions. It is a probable bacteriocin-like metabolite biosynthesis protein. [Cellular processes, Toxin production and resistance]

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 71988619      3 MEGCNLRDIgKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVCTLKLIDFG 70
Cdd:TIGR03903   61 VPGRTLREV-LAADGALPAGETGRLMLQVLDALACAHNQGIVHRDLKPQNIMVSQTGVRPHAKVLDFG 127

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 MEGCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFGKAIRIKDQNGNQ 82
Cdd:cd00180  73 CEGGSLKDLLKENKGPLSEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDG---TVKLADFGLAKDLDSDDSLL 149

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 71988619  83 LPGHQDGIDYsrcsQHSVNVILGIAPTQNDDWSSLVYLLMKMRGF 127
Cdd:cd00180 150 KTTGGTTPPY----YAPPELLGGRYYGPKVDIWSLGVILYELEEL 190

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. Some isoforms have several splice variants such as the long (L) and short (S) variants of CK1alpha. CK1 proteins are involved in the regulation of many cellular processes including membrane transport processes, circadian rhythm, cell division, apoptosis, and the development of cancer and neurodegenerative diseases. The CK1 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   1 MSME--GCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVCTLKLIDFGKAIRIKDQ 78
Cdd:cd14016  73 MVMDllGPSLEDLFNKCGRKFSLKTVLMLADQMISRLEYLHSKGYIHRDIKPENFLMGLGKNSNKVYLIDFGLAKKYRDP 152

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 71988619  79 NGNQlpgHqdgIDYSRCSQH-------SVNVILGIAPTQNDDWSSLVYLLM 122
Cdd:cd14016 153 RTGK---H---IPYREGKSLtgtaryaSINAHLGIEQSRRDDLESLGYVLI 197

Serine/Threonine protein kinases, catalytic domain; Phosphotransferases. Serine or threonine-specific kinase subfamily.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 71988619      3 MEGCNLRDIGKQTpGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKAIRIKD 77
Cdd:smart00220  79 CEGGDLFDLLKKR-GRLSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILL---DEDGHVKLADFGLARQLDP 149

Catalytic domain of Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase-like Serine/Threonine kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed mainly of MAP3Ks and similar proteins, including TGF-beta Activated Kinase-1 (TAK1, also called MAP3K7), MAP3K12, MAP3K13, Mixed lineage kinase (MLK), MLK-Like mitogen-activated protein Triple Kinase (MLTK), and Raf (Rapidly Accelerated Fibrosarcoma) kinases. MAP3Ks (MKKKs or MAPKKKs) phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Also included in this subfamily is the pseudokinase Kinase Suppressor of Ras (KSR), which is a scaffold protein that functions downstream of Ras and upstream of Raf in the Extracellular signal-Regulated Kinase (ERK) pathway.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 MEGCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKAiRIKDQNGNQ 82
Cdd:cd13999  72 MPGGSLYDLLHKKKIPLSWSLRLKIALDIARGMNYLHSPPIIHRDLKSLNILL---DENFTVKIADFGLS-RIKNSTTEK 147

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase Kinase Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPKKKs (MKKKs or MAP3Ks) are also called MAP/ERK kinase kinases (MEKKs) in some cases. They phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. This subfamily is composed of the Apoptosis Signal-regulating Kinases ASK1 (or MAPKKK5) and ASK2 (or MAPKKK6), MEKK1, MEKK2, MEKK3, MEKK4, as well as plant and fungal MAPKKKs. Also included in this subfamily are the cell division control proteins Schizosaccharomyces pombe Cdc7 and Saccharomyces cerevisiae Cdc15. The MAPKKK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 ME---GCNLRDIGKQTpGRLSfNNLMRVaYT----LGntLCYIHDRGFIHRDLKADNVVVTFSnevCTLKLIDFGKAIRI 75
Cdd:cd06606  78 LEyvpGGSLASLLKKF-GKLP-EPVVRK-YTrqilEG--LEYLHSNGIVHRDIKGANILVDSD---GVVKLADFGCAKRL 149

                ..
gi 71988619  76 KD 77
Cdd:cd06606 150 AE 151

The catalytic domain of CAMK family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CaMKs are multifunctional calcium and calmodulin (CaM) stimulated STKs involved in cell cycle regulation. There are several types of CaMKs including CaMKI, CaMKII, and CaMKIV. CaMKI proteins are monomeric and they play pivotal roles in the nervous system, including long-term potentiation, dendritic arborization, neurite outgrowth, and the formation of spines, synapses, and axons. CaMKII is a signaling molecule that translates upstream calcium and reactive oxygen species (ROS) signals into downstream responses that play important roles in synaptic function and cardiovascular physiology. CAMKIV is implicated in regulating several transcription factors like CREB, MEF2, and retinoid orphan receptors, as well as in T-cell development and signaling. The CAMK family also consists of other related kinases including the Phosphorylase kinase Gamma subunit (PhKG), the C-terminal kinase domains of Ribosomal S6 kinase (RSK) and Mitogen and stress-activated kinase (MSK), Doublecortin-like kinase (DCKL), and the MAPK-activated protein kinases MK2, MK3, and MK5, among others. The CAMK family is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 71988619  27 VAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVCTLKLIDFGKAIRIKDQN 79
Cdd:cd05117 104 IMKQILSAVAYLHSQGIVHRDLKPENILLASKDPDSPIKIIDFGLAKIFEEGE 156

Catalytic domain of Fungal Halotolerance protein 4-like Serine/Threonine kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of HAL4, Saccharomyces cerevisiae Ptk2/Stk2, and similar fungal proteins. Proteins in this subfamily are involved in regulating ion transporters. In budding and fission yeast, HAL4 promotes potassium ion uptake, which increases cellular resistance to other cations such as sodium, lithium, and calcium ions. HAL4 stabilizes the major high-affinity K+ transporter Trk1 at the plasma membrane under low K+ conditions, which prevents endocytosis and vacuolar degradation. Budding yeast Ptk2 phosphorylates and regulates the plasma membrane H+ ATPase, Pma1. The HAL4-like subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 71988619  37 YIHDRGFIHRDLKADNVVVTfsnEVCTLKLIDFGKAIRIKDQNGNQLPgHQDGI 90
Cdd:cd13994 113 YLHSHGIAHRDLKPENILLD---EDGVLKLTDFGTAEVFGMPAEKESP-MSAGL 162

Catalytic domain of the Serine/Threonine protein kinase, Vaccinia Related Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins (VRK1, VRK2, and VRK3) while invertebrates, specifically fruit flies and nematodes, seem to carry only a single ortholog. Mutations of VRK in Drosophila and Caenorhabditis elegans showed varying phenotypes ranging from embryonic lethality to mitotic and meiotic defects resulting in sterility. In vertebrates, VRK1 is implicated in cell cycle progression and proliferation, nuclear envelope assembly, and chromatin condensation. VRK2 is involved in modulating JNK signaling. VRK3 is an inactive pseudokinase that inhibits ERK signaling. The VRK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   1 MSME--GCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVCTLKLIDFGKAIRIKDq 78
Cdd:cd14015 104 LVMPrfGRDLQKIFEKNGKRFPEKTVLQLALRILDVLEYIHENGYVHADIKASNLLLGFGKNKDQVYLVDYGLASRYCP- 182

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 71988619  79 NGNQLP-------GHQDGIDYSRCSQHsvnviLGIAPTQNDDWSSLVYLLMK 123
Cdd:cd14015 183 NGKHKEykedprkAHNGTIEFTSRDAH-----KGVAPSRRGDLEILGYNMLQ 229

Catalytic domain of the Serine/Threonine Kinase, p38beta Mitogen-Activated Protein Kinase (also called MAPK11); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. p38beta/MAPK11 is widely expressed in tissues and shows more similarity with p38alpha than with the other isoforms. Both are sensitive to pyridinylimidazoles and share some common substrates such as MAPK activated protein kinase 2 (MK2) and the transcription factors ATF2, c-Fos and, ELK-1. p38beta is involved in regulating the activation of the cyclooxygenase-2 promoter and the expression of TGFbeta-induced alpha-smooth muscle cell actin. p38 kinases are mitogen-activated protein kinases (MAPKs), serving as important mediators of cellular responses to extracellular signals. They are activated by the MAPK kinases MKK3 and MKK6, which in turn are activated by upstream MAPK kinase kinases including TAK1, ASK1, and MLK3, in response to cellular stresses or inflammatory cytokines. The p38beta subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71988619   2 SMEGCNLRDIGKQTpgRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKAIRIKDQ 78
Cdd:cd07878 100 NLMGADLNNIVKCQ--KLSDEHVQFLIYQLLRGLKYIHSAGIIHRDLKPSNVAV---NEDCELRILDFGLARQADDE 171

Tyrosine kinase, catalytic domain; Phosphotransferases. Tyrosine-specific kinase subfamily.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 71988619      3 MEGCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVctlKLIDFGKAIRIKD 77
Cdd:smart00219  83 MEGGDLLSYLRKNRPKLSLSDLLSFALQIARGMEYLESKNFIHRDLAARNCLVGENLVV---KISDFGLSRDLYD 154

Catalytic domain of the Serine/Threonine Kinase, c-Jun N-terminal Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. JNKs are mitogen-activated protein kinases (MAPKs) that are involved in many stress-activated responses including those during inflammation, neurodegeneration, apoptosis, and persistent pain sensitization, among others. They are also essential regulators of physiological and pathological processes and are involved in the pathogenesis of several diseases such as diabetes, atherosclerosis, stroke, Parkinson's and Alzheimer's. Vetebrates harbor three different JNK genes (Jnk1, Jnk2, and Jnk3) that are alternatively spliced to produce at least 10 isoforms. JNKs are specifically activated by the MAPK kinases MKK4 and MKK7, which are in turn activated by upstream MAPK kinase kinases as a result of different stimuli including stresses such as ultraviolet (UV) irradiation, hyperosmolarity, heat shock, or cytokines. JNKs activate a large number of different substrates based on specific stimulus, cell type, and cellular condition, and may be implicated in seemingly contradictory functions. The JNK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 71988619  26 RVAYTLGNTLC---YIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKA 72
Cdd:cd07850 103 RMSYLLYQMLCgikHLHSAGIIHRDLKPSNIVV---KSDCTLKILDFGLA 149

C-terminal catalytic domain of the Serine/Threonine Kinase, Mitogen and stress-activated kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. MSKs are activated by two major signaling cascades, the Ras-MAPK and p38 stress kinase pathways, in response to various stimuli such as growth factors, hormones, neurotransmitters, cellular stress, and pro-inflammatory cytokines. This triggers phosphorylation in the activation loop (A-loop) of the CTD of MSK. The active CTD phosphorylates the hydrophobic motif (HM) in the C-terminal extension of NTD, which facilitates the phosphorylation of the A-loop and activates the NTD, which in turn phosphorylates downstream targets. MSKs are predominantly nuclear proteins. They are widely expressed in many tissues including heart, brain, lung, liver, kidney, and pancreas. There are two isoforms of MSK, called MSK1 and MSK2. The MSK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 71988619  37 YIHDRGFIHRDLKADNVVVTFSNEVCTLKLIDFGKAiRIKDQN 79
Cdd:cd14092 114 FMHSKGVVHRDLKPENLLFTDEDDDAEIKIVDFGFA-RLKPEN 155

Catalytic domain of Rho-associated coiled-coil containing protein kinase (ROCK)- and Nuclear Dbf2-Related (NDR)-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this subfamily include ROCK and ROCK-like proteins such as DMPK, MRCK, and CRIK, as well as NDR and NDR-like proteins such as LATS, CBK1 and Sid2p. ROCK and CRIK are effectors of the small GTPase Rho, while MRCK is an effector of the small GTPase Cdc42. NDR and NDR-like kinases contain an N-terminal regulatory (NTR) domain and an insert within the catalytic domain that contains an auto-inhibitory sequence. Proteins in this subfamily are involved in regulating many cellular functions including contraction, motility, division, proliferation, apoptosis, morphogenesis, and cytokinesis. The ROCK/NDR-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619  37 YIHDRGFIHRDLKADNVVVTFSNEVctlKLIDFGKAIRIKD-------QNGNQLPGHQDGIDYSRCSQ----HSVNVILG 105
Cdd:cd05573 116 SLHKLGFIHRDIKPDNILLDADGHI---KLADFGLCTKMNKsgdresyLNDSVNTLFQDNVLARRRPHkqrrVRAYSAVG 192

                        90       100
                ....*....|....*....|....
gi 71988619 106 ----IAP--------TQNDDWSSL 117
Cdd:cd05573 193 tpdyIAPevlrgtgyGPECDWWSL 216

Catalytic domain of the Serine/Threonine protein kinase, Vaccinia Related Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins. VRK2 exists as two alternative splice forms, A and B, which differ in their C-terminal regions. VRK2A, the predominant isoform, contains a hydrophobic tail and is anchored to the ER and mitochondria. It is expressed in all cell types. VRK2B lacks a membrane-anchor tail and is detected in the cytosol and the nucleus. Like VRK1, it can stabilize p53. VRK2B functionally replaces VRK1 in the nucleus of cell types where VRK1 is absent. VRK2 modulates hypoxia-induced stress responses by interacting with TAK1, an atypical MAPK kinase kinase which triggers cascades that activate JNK following oxidative stress. VRK2 also interacts with JIP1, a scaffold protein that assembles three consecutive members of a MAPK pathway. This interaction prevents the association of JNK with the signaling complex, leading to reduced phosphorylation and AP1-dependent transcription. The VRK2 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   1 MSME--GCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVcTLKLIDFGKAIRI--- 75
Cdd:cd14123 106 MVMDrlGTDLQKILIDNGGQFKKTTVLQLGIRMLDVLEYIHENEYVHGDIKAANLLLGYRNPN-EVYLADYGLSYRYcpn 184

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 71988619  76 ---KDQNGNQLPGHQDGIDYSRCSQHSvnvilGIAPTQNDDWSSLVYLLM 122
Cdd:cd14123 185 gnhKEYKENPRKGHNGTIEFTSLDAHK-----GVAPSRRGDLEILGYCML 229

Catalytic domain of the Protein Tyrosine Kinase, Fibroblast Growth Factor Receptor 4; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Unlike other FGFRs, there is only one splice form of FGFR4. It binds FGF1, FGF2, FGF6, FGF19, and FGF23. FGF19 is a selective ligand for FGFR4. Although disruption of FGFR4 in mice causes no obvious phenotype, in vivo inhibition of FGFR4 in cultured skeletal muscle cells resulted in an arrest of muscle progenitor differentiation. FGF6 and FGFR4 are uniquely expressed in myofibers and satellite cells. FGF6/FGFR4 signaling appears to play a key role in the regulation of muscle regeneration. A polymorphism in FGFR4 is found in head and neck squamous cell carcinoma. FGFR4 is part of the FGFR subfamily, which are receptor PTKs (RTKs) containing an extracellular ligand-binding region with three immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. The binding of FGFRs to their ligands, the FGFs, results in receptor dimerization and activation, and intracellular signaling. The binding of FGFs to FGFRs is promiscuous, in that a receptor may be activated by several ligands and a ligand may bind to more that one type of receptor. The FGFR4 subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619  10 DIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFGKAIRIKDqngnqlpghqdg 89
Cdd:cd05099 122 DITKVPEEQLSFKDLVSCAYQVARGMEYLESRRCIHRDLAARNVLVTEDN---VMKIADFGLARGVHD------------ 186

                        90       100       110
                ....*....|....*....|....*....|....*
gi 71988619  90 IDYSRCSQHSVNVILGIAPT---------QNDDWS 115
Cdd:cd05099 187 IDYYKKTSNGRLPVKWMAPEalfdrvythQSDVWS 221

Catalytic domain of the Serine/Threonine Kinase, p38 Mitogen-Activated Protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. p38 kinases are mitogen-activated protein kinases (MAPKs), serving as important mediators of cellular responses to extracellular signals. They function in the regulation of the cell cycle, cell development, cell differentiation, senescence, tumorigenesis, apoptosis, pain development and pain progression, and immune responses. p38 kinases are activated by the MAPK kinases MKK3 and MKK6, which in turn are activated by upstream MAPK kinase kinases including TAK1, ASK1, and MLK3, in response to cellular stresses or inflammatory cytokines. p38 substrates include other protein kinases and factors that regulate transcription, nuclear export, mRNA stability and translation. p38 kinases are drug targets for the inflammatory diseases psoriasis, rheumatoid arthritis, and chronic pulmonary disease. Vertebrates contain four isoforms of p38, named alpha, beta, gamma, and delta, which show varying substrate specificity and expression patterns. p38alpha and p38beta are ubiquitously expressed, p38gamma is predominantly found in skeletal muscle, and p38delta is found in the heart, lung, testis, pancreas, and small intestine. The p38 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 71988619  18 RLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKA 72
Cdd:cd07851 114 KLSDDHIQFLVYQILRGLKYIHSAGIIHRDLKPSNLAV---NEDCELKILDFGLA 165

Pseudokinase domain of Vaccinia Related Kinase 3; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins. VRK3 is an inactive pseudokinase that is unable to bind ATP. It achieves its regulatory function through protein-protein interactions. It negatively regulates ERK signaling by binding directly and enhancing the activity of the MAPK phosphatase VHR (vaccinia H1-related), which dephosphorylates and inactivates ERK. The VRK3 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   5 GCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTfSNEVCTLKLIDFGKAIR-------IKD 77
Cdd:cd14124 105 GQSLQSALDEGKGVLSEKAVLQLACRLLDALEFIHENEYVHGDITAENIFVD-PEDQSEVYLAGYGFAFRycpggkhVEY 183

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619  78 QNGNQLPgHQDGIDYSRCSQHSvnvilGIAPTQNDDWSSLVYLLMK-MRGF-SWGD---TAEEMLDLKVQFENDPKDMIA 152
Cdd:cd14124 184 REGSRSP-HEGDIEFISLDSHK-----GAGPSRRSDLQSLGYCMLKwLTGSlPWSNllhNTEDIMKQKERFMDDVPGFLG 257

                ....*..
gi 71988619 153 QDMMWMR 159
Cdd:cd14124 258 PCFHQKK 264

Catalytic domain of the Protein Tyrosine Kinases, Lymphocyte-specific kinase and Blk; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Lck and Blk are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Blk is expressed specifically in B-cells. It is involved in pre-BCR (B-cell receptor) signaling. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Lck/Blk subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 MEGCNLRDIGKQTPG-RLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTfsnEVCTLKLIDFGKAIRIKD---- 77
Cdd:cd05067  83 MENGSLVDFLKTPSGiKLTINKLLDMAAQIAEGMAFIEERNYIHRDLRAANILVS---DTLSCKIADFGLARLIEDneyt 159

                ....*...
gi 71988619  78 -QNGNQLP 84
Cdd:cd05067 160 aREGAKFP 167

Catalytic domain of the Serine/Threonine Kinase, PFTAIRE-2 kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PFTAIRE-2 is also referred to as ALS2CR7 (amyotrophic lateral sclerosis 2 (juvenile) chromosome region candidate 7). It may be associated with amyotrophic lateral sclerosis 2 (ALS2), an autosomal recessive form of juvenile ALS. The function of PFTAIRE-2 is not yet known. It shares sequence similarity with Cyclin-Dependent Kinases (CDKs), which belong to a large family of STKs that are regulated by their cognate cyclins. Together, CDKs and cyclins are involved in the control of cell-cycle progression, transcription, and neuronal function. The PFTAIRE-2 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 71988619  14 QTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEvctLKLIDFGKA 72
Cdd:cd07870  90 QHPGGLHPYNVRLFMFQLLRGLAYIHGQHILHRDLKPQNLLISYLGE---LKLADFGLA 145

Catalytic domain of Cell division control protein 7-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this subfamily include Schizosaccharomyces pombe Cdc7, Saccharomyces cerevisiae Cdc15, Arabidopsis thaliana mitogen-activated protein kinase kinase kinase (MAPKKK) epsilon, and related proteins. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Fission yeast Cdc7 is essential for cell division by playing a key role in the initiation of septum formation and cytokinesis. Budding yeast Cdc15 functions to coordinate mitotic exit with cytokinesis. Arabidopsis MAPKKK epsilon is required for pollen development in the plasma membrane. The Cdc7-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 71988619  35 LCYIHDRGFIHRDLKADNVVVTFSNEVctlKLIDFGKAIRIKD 77
Cdd:cd06627 112 LAYLHEQGVIHRDIKGANILTTKDGLV---KLADFGVATKLNE 151

Catalytic domain of the Serine/Threonine Kinase, p21-activated kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. PAKs are implicated in the regulation of many cellular processes including growth factor receptor-mediated proliferation, cell polarity, cell motility, cell death and survival, and actin cytoskeleton organization. PAK deregulation is associated with tumor development. PAKs from higher eukaryotes are classified into two groups (I and II), according to their biochemical and structural features. Group I PAKs contain a PBD (p21-binding domain) overlapping with an AID (autoinhibitory domain), a C-terminal catalytic domain, SH3 binding sites and a non-classical SH3 binding site for PIX (PAK-interacting exchange factor). Group II PAKs contain a PBD and a catalytic domain, but lack other motifs found in group I PAKs. Since group II PAKs do not contain an obvious AID, they may be regulated differently from group I PAKs. Group I PAKs interact with the SH3 containing proteins Nck, Grb2 and PIX; no such binding has been demonstrated for group II PAKs. The PAK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619   3 MEGCNLRDIGKQTPGRLsfnNLMRVAYTLGNT---LCYIHDRGFIHRDLKADNVVVTFSNEVctlKLIDFGKAIRIKDQN 79
Cdd:cd06614  78 MDGGSLTDIITQNPVRM---NESQIAYVCREVlqgLEYLHSQNVIHRDIKSDNILLSKDGSV---KLADFGFAAQLTKEK 151

                ..
gi 71988619  80 GN 81
Cdd:cd06614 152 SK 153

Catalytic domain of Dual-specificity tYrosine-phosphorylated and -Regulated Kinase-like protein kinases; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (S/T) as well as tyrosine residues on protein substrates. This subfamily is composed of the dual-specificity DYRKs and YAK1, as well as the S/T kinases (STKs), HIPKs. DYRKs and YAK1 autophosphorylate themselves on tyrosine residues and phosphorylate their substrates exclusively on S/T residues. Proteins in this subfamily play important roles in cell proliferation, differentiation, survival, growth, and development. The DYRK-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 71988619   3 MEGCNLRDIGKQT--PGrLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTfSNEVCTLKLIDFGKA 72
Cdd:cd14133  82 LLSQNLYEFLKQNkfQY-LSLPRIRKIAQQILEALVFLHSLGLIHCDLKPENILLA-SYSRCQIKIIDFGSS 151

Catalytic domain of the Serine/Threonine kinases, Mitogen-activated protein kinase signal-integrating kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPK signal-integrating kinases (Mnks) are MAPK-activated protein kinases and is comprised by a group of four proteins, produced by alternative splicing from two genes (Mnk1 and Mnk2). The isoforms of Mnk1 (1a/1b) and Mnk2 (2a/2b) differ at their C-termini, with the a-form having a longer C-terminus containing a MAPK-binding region. All Mnks contain a catalytic kinase domain and a polybasic region at the N-terminus which binds importin and the eukaryotic initiation factor eIF4G. The best characterized Mnk substrate is eIF4G, whose phosphorylation may promote the export of certain mRNAs from the nucleus. Mnk also phosphorylate substrates that bind to AU-rich elements that regulate mRNA stability and translation. Mnks have also been implicated in tyrosine kinase receptor signaling, inflammation, and cell prolieration or survival. The Mnk subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 71988619  26 RVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVCTLKLIDFGKAIRIKDQNGNQLP 84
Cdd:cd14090 104 LVVRDIASALDFLHDKGIAHRDLKPENILCESMDKVSPVKICDFDLGSGIKLSSTSMTP 162

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase 15 and similar MAPKs; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Human MAPK15 is also called Extracellular signal Regulated Kinase 8 (ERK8) while the rat protein is called ERK7. ERK7 and ERK8 display both similar and different biochemical properties. They autophosphorylate and activate themselves and do not require upstream activating kinases. ERK7 is constitutively active and is not affected by extracellular stimuli whereas ERK8 shows low basal activity and is activated by DNA-damaging agents. ERK7 and ERK8 also have different substrate profiles. Genome analysis shows that they are orthologs with similar gene structures. ERK7 and ERK 8 may be involved in the signaling of some nuclear receptor transcription factors. ERK7 regulates hormone-dependent degradation of estrogen receptor alpha while ERK8 down-regulates the transcriptional co-activation androgen and glucocorticoid receptors. MAPKs are important mediators of cellular responses to extracellular signals. The MAPK15 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 71988619  27 VAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKA 72
Cdd:cd07852 112 IMYQLLKALKYLHSGGVIHRDLKPSNILL---NSDCRVKLADFGLA 154

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPKs serve as important mediators of cellular responses to extracellular signals. They control critical cellular functions including differentiation, proliferation, migration, and apoptosis. They are also implicated in the pathogenesis of many diseases including multiple types of cancer, stroke, diabetes, and chronic inflammation. Typical MAPK pathways involve a triple kinase core cascade comprising of the MAPK, which is phosphorylated and activated by a MAPK kinase (MAP2K or MKK), which itself is phosphorylated and activated by a MAPK kinase kinase (MAP3K or MKKK). Each cascade is activated either by a small GTP-binding protein or by an adaptor protein, which transmits the signal either directly to a MAP3K to start the triple kinase core cascade or indirectly through a mediator kinase, a MAP4K. There are three typical MAPK subfamilies: Extracellular signal-Regulated Kinase (ERK), c-Jun N-terminal Kinase (JNK), and p38. Some MAPKs are atypical in that they are not regulated by MAP2Ks. These include MAPK4, MAPK6, NLK, and ERK7. The MAPK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 71988619  37 YIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKAiRIKDQNGNQ 82
Cdd:cd07834 118 YLHSAGVIHRDLKPSNILV---NSNCDLKICDFGLA-RGVDPDEDK 159

Catalytic domain of the Serine/Threonine Kinase, p21-activated kinase 6; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PAK6 may play a role in stress responses through its activation by the mitogen-activated protein kinase (MAPK) p38 and MAPK kinase 6 (MKK6) pathway. PAK6 is highly expressed in the brain. It is not required for viability, but together with PAK5, it is required for normal levels of locomotion and activity, and for learning and memory. Increased expression of PAK6 is found in primary and metastatic prostate cancer. PAK6 may play a role in the regulation of motility. PAK6 belongs to the group II PAKs, which contain a PBD (p21-binding domain) and a C-terminal catalytic domain, but do not harbor an AID (autoinhibitory domain) or SH3 binding sites. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. The PAK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 71988619   3 MEGCNLRDIGKQTpgRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNEVctlKLIDFGKAIRI-KD 77
Cdd:cd06659 100 LQGGALTDIVSQT--RLNEEQIATVCEAVLQALAYLHSQGVIHRDIKSDSILLTLDGRV---KLSDFGFCAQIsKD 170

Catalytic domain of Microtubule-associated serine/threonine (MAST) kinase-like proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes MAST kinases, MAST-like (MASTL) kinases (also called greatwall kinase or Gwl), and fungal kinases with similarity to Saccharomyces cerevisiae Rim15 and Schizosaccharomyces pombe cek1. MAST kinases contain an N-terminal domain of unknown function, a central catalytic domain, and a C-terminal PDZ domain that mediates protein-protein interactions. MASTL kinases carry only a catalytic domain which contains a long insert relative to other kinases. The fungal kinases in this subfamily harbor other domains in addition to a central catalytic domain, which like in MASTL, also contains an insert relative to MAST kinases. Rim15 contains a C-terminal signal receiver (REC) domain while cek1 contains an N-terminal PAS domain. MAST kinases are cytoskeletal associated kinases of unknown function that are also expressed at neuromuscular junctions and postsynaptic densities. MASTL/Gwl is involved in the regulation of mitotic entry, mRNA stabilization, and DNA checkpoint recovery. The fungal proteins Rim15 and cek1 are involved in the regulation of meiosis and mitosis, respectively. The MAST-like kinase subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 71988619  35 LCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFG 70
Cdd:cd05579 106 LEYLHSHGIIHRDLKPDNILIDANG---HLKLTDFG 138

Catalytic domain of the Serine/Threonine kinases, Liver Kinase B1, Calmodulin Dependent Protein Kinase Kinase, and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Both LKB1 and CaMKKs can phosphorylate and activate AMP-activated protein kinase (AMPK). LKB1, also called STK11, serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. LKB1 and AMPK are part of an energy-sensing pathway that links cell energy to metabolism and cell growth. They play critical roles in the establishment and maintenance of cell polarity, cell proliferation, cytoskeletal organization, as well as T-cell metabolism, including T-cell development, homeostasis, and effector function. CaMKKs are upstream kinases of the CaM kinase cascade that phosphorylate and activate CaMKI and CamKIV. They may also phosphorylate other substrates including PKB and AMPK. Vertebrates contain two CaMKKs, CaMKK1 (or alpha) and CaMKK2 (or beta). CaMKK1 is involved in the regulation of glucose uptake in skeletal muscles. CaMKK2 is involved in regulating energy balance, glucose metabolism, adiposity, hematopoiesis, inflammation, and cancer. The LKB1/CaMKK subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 71988619   1 MSME----GCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFG 70
Cdd:cd14008  83 LVLEycegGPVMELDSGDRVPPLPEETARKYFRDLVLGLEYLHENGIVHRDIKPENLLLTADG---TVKISDFG 153

Catalytic domain of PCTAIRE-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PCTAIRE-like proteins show unusual expression patterns with high levels in post-mitotic tissues, suggesting that they may be involved in regulating post-mitotic cellular events. They share sequence similarity with Cyclin-Dependent Kinases (CDKs), which belong to a large family of STKs that are regulated by their cognate cyclins. Together, CDKs and cyclins are involved in the control of cell-cycle progression, transcription, and neuronal function. The association of PCTAIRE-like proteins with cyclins has not been widely studied, although PFTAIRE-1 has been shown to function as a CDK which is regulated by cyclin D3 as well as the membrane-associated cyclin Y. The PCTAIRE-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 71988619  16 PGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVtfsNEVCTLKLIDFGKA 72
Cdd:cd07844  92 GGGLSMHNVRLFLFQLLRGLAYCHQRRVLHRDLKPQNLLI---SERGELKLADFGLA 145

Catalytic domain of Cyclin-Dependent protein Kinase Like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of CDKL1-5 and similar proteins. Some CDKLs, like CDKL1 and CDKL3, may be implicated in transformation and others, like CDKL3 and CDKL5, are associated with mental retardation when impaired. CDKL2 plays a role in learning and memory. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDKL subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 71988619   1 MSME--GCNLRDIGKQTPGRLSFNNLMRVAYTLGNTLCYIHDRGFIHRDLKADNVVVTFSNevcTLKLIDFGKA 72
Cdd:cd07833  77 LVFEyvERTLLELLEASPGGLPPDAVRSYIWQLLQAIAYCHSHNIIHRDIKPENILVSESG---VLKLCDFGFA 147

Catalytic domain of the Serine/Threonine Kinase, c-Jun N-terminal Kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. JNK2 is expressed in every cell and tissue type. It is specifically translocated to the mitochondria during dopaminergic cell death. Specific substrates include the microtubule-associated proteins DCX and Tau, as well as TIF-IA which is involved in ribosomal RNA synthesis regulation. Mice deficient in Jnk2 show protection against arthritis, type 1 diabetes, atherosclerosis, abdominal aortic aneurysm, cardiac cell death, TNF-induced liver damage, and tumor growth, indicating that JNK2 may play roles in the pathogenesis of these diseases. Initially it was thought that JNK1 and JNK2 were functionally redundant as mice deficient in either genes could survive but disruption of both genes resulted in lethality. However, recent studies have shown that JNK1 and JNK2 perform distinct functions through specific binding partners and substrates. JNKs are mitogen-activated protein kinases (MAPKs) that are involved in many stress-activated responses including those during inflammation, neurodegeneration, apoptosis, and persistent pain sensitization, among others. The JNK2 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71988619  26 RVAYTLGNTLC---YIHDRGFIHRDLKADNVVVTFSnevCTLKLIDFGKAiRIKDQNGNQLPghQDGIDYSRCSQhsvnV 102
Cdd:cd07876 124 RMSYLLYQMLCgikHLHSAGIIHRDLKPSNIVVKSD---CTLKILDFGLA-RTACTNFMMTP--YVVTRYYRAPE----V 193

                        90
                ....*....|....
gi 71988619 103 ILGIAPTQN-DDWS 115
Cdd:cd07876 194 ILGMGYKENvDIWS 207

C-terminal catalytic domain of the Serine/Threonine Kinase, Ribosomal S6 kinase 1 (also called Ribosomal protein S6 kinase alpha-1 or 90kDa ribosomal protein S6 kinase 1); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RSK1 is also called S6K-alpha-1, RPS6KA1, p90RSK1 or MAPK-activated protein kinase 1a (MAPKAPK-1a). It is a component of the insulin transduction pathway, regulating the function of IRS1. It also interacts with PKA and promotes its inactivation. RSK1 is one of four RSK isoforms (RSK1-4) from distinct genes present in vertebrates. RSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. They are activated by signaling inputs from extracellular regulated kinase (ERK) and phosphoinositide dependent kinase 1 (PDK1). ERK phosphorylates and activates the CTD of RSK, serving as a docking site for PDK1, which phosphorylates and activates the NTD, which in turn phosphorylates all known RSK substrates. RSKs act as downstream effectors of mitogen-activated protein kinase (MAPK) and play key roles in mitogen-activated cell growth, differentiation, and survival. The RSK1 subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 71988619  27 VAYTLGNTLCYIHDRGFIHRDLKADNVV-VTFSNEVCTLKLIDFGKAIRIKDQNG 80
Cdd:cd14175 100 VLHTICKTVEYLHSQGVVHRDLKPSNILyVDESGNPESLRICDFGFAKQLRAENG 154

Catalytic domain of Cyclin-Dependent protein Kinase 9-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of CDK9 and CDK12 from higher eukaryotes, yeast BUR1, C-type plant CDKs (CdkC), and similar proteins. CDK9, BUR1, and CdkC are functionally equivalent. They act as a kinase for the C-terminal domain of RNA polymerase II and participate in regulating mutliple steps of gene expression including transcription elongation and RNA processing. CDK9 and CdkC associate with T-type cyclins while BUR1 associates with the cyclin BUR2. CDK12 is a unique CDK that contains an arginine/serine-rich (RS) domain, which is predominantly found in splicing factors. CDK12 interacts with cyclins L1 and L2, and participates in regulating transcription and alternative splicing. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. The CDK9-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 71988619  35 LCYIHDRGFIHRDLKADNVVVTFSNEvctLKLIDFGKA 72
Cdd:cd07840 117 LQYLHSNGILHRDIKGSNILINNDGV---LKLADFGLA 151