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 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDCWIEDPKLGKVTLEIAILSRVE---HANIIKVLDIFENQ 1074
Cdd:cd14004     1 DYTILKEMGEGAYGQVNLAIYKSKGKEVVIKFIFKERILVDTWVRDRKLGTVPLEIHILDTLNkrsHPNIVKLLDFFEDD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 355477269 1075 GFFQLVMEKHGSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14004    81 EFYYLVMEKHGSGMDLFDFIERKPNMDEKEAKYIFRQVADA 121

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 355477269    344 TISGLITLLPDGTIHGINHSfALTLFGYGKTELLGKNITFLIPGFYSYMDLAYNSSLQ 401
Cdd:smart00091   10 LPDGIFVLDLDGRILYANPA-AEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLL 66

Catalytic domain of the Serine/Threonine kinase, Per-ARNT-Sim (PAS) domain Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PASK (or PASKIN) is a nutrient and energy sensor and thus, plays an important role in maintaining cellular energy homeostasis. It coordinates the utilization of glucose in response to metabolic demand. It contains an N-terminal PAS domain which directly interacts and inhibits a C-terminal catalytic kinase domain. The PAS domain serves as a sensory module for different environmental signals such as light, redox state, and various metabolites. Binding of ligands to the PAS domain causes structural changes which leads to kinase activation and the phosphorylation of substrates to trigger the appropriate cellular response. The PASK 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 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDCWIEDPKLGKVTLEIAILSRVE---HANIIKVLDIFENQ 1074
Cdd:cd14004     1 DYTILKEMGEGAYGQVNLAIYKSKGKEVVIKFIFKERILVDTWVRDRKLGTVPLEIHILDTLNkrsHPNIVKLLDFFEDD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 355477269 1075 GFFQLVMEKHGSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14004    81 EFYYLVMEKHGSGMDLFDFIERKPNMDEKEAKYIFRQVADA 121

Protein kinase domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269   999 YSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDcwiedpKLGKVTLEIAILSRVEHANIIKVLDIFENQGFFQ 1078
Cdd:pfam00069    1 YEVLRKLGSGSFGTVYKAKHRDTGKIVAIKKIKKEKIKKK------KDKNILREIKILKKLNHPNIVRLYDAFEDKDNLY 74

                           90       100       110
                   ....*....|....*....|....*....|....
gi 355477269  1079 LVMEkHGSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:pfam00069   75 LVLE-YVEGGSLFDLLSEKGAFSEREAKFIMKQI 107

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269  133 AIFTVDAKTTeILVANDKACGLLGYSSQDLIGQKLTQFFLRSDSDVVEalsEEHMEADgHAAVVFGTVVDIISRSGEKIP 212
Cdd:cd00130     4 GVIVLDLDGR-ILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELR---ERLENLL-SGGEPVTLEVRLRRKDGSVIW 78

                          90       100
                  ....*....|....*....|
gi 355477269  213 VSVWMKRMRQERRLCCVVVL 232
Cdd:cd00130    79 VLVSLTPIRDEGGEVIGLLG 98

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*.
gi 355477269    133 AIFTVDAKTTeILVANDKACGLLGYSSQDLIGQKLTQFFLRSDSDVVEALSEEHME 188
Cdd:smart00091   13 GIFVLDLDGR-ILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLLS 67

PAS domain S-box; The PAS domain was previously described. This sensory box, or S-box domain occupies the central portion of the PAS domain but is more widely distributed. It is often tandemly repeated. Known prosthetic groups bound in the S-box domain include heme in the oxygen sensor FixL, FAD in the redox potential sensor NifL, and a 4-hydroxycinnamyl chromophore in photoactive yellow protein. Proteins containing the domain often contain other regulatory domains such as response regulator or sensor histidine kinase domains. Other S-box proteins include phytochromes and the aryl hydrocarbon receptor nuclear translocator. [Regulatory functions, Small molecule interactions]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269   129 NPNKAIFTVDAKTTeILVANDKACGLLGYSSQDLIGQKLTQFFLRSDSDVVEALSEEHMEADGHaavVFGTVVDIISRSG 208
Cdd:TIGR00229   11 SSPDAIIVIDLEGN-ILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIERRLEGEPE---PVSEERRVRRKDG 86

                           90
                   ....*....|....
gi 355477269   209 EKIPVSVWMKRMRQ 222
Cdd:TIGR00229   87 SEIWVEVSVSPIRT 100

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*...
gi 355477269    344 TISGLITLLPDGTIHGINHSfALTLFGYGKTELLGKNITFLIPGFYSYMDLAYNSSLQ 401
Cdd:smart00091   10 LPDGIFVLDLDGRILYANPA-AEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLL 66

Catalytic domain of the Serine/Threonine kinase, Per-ARNT-Sim (PAS) domain Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PASK (or PASKIN) is a nutrient and energy sensor and thus, plays an important role in maintaining cellular energy homeostasis. It coordinates the utilization of glucose in response to metabolic demand. It contains an N-terminal PAS domain which directly interacts and inhibits a C-terminal catalytic kinase domain. The PAS domain serves as a sensory module for different environmental signals such as light, redox state, and various metabolites. Binding of ligands to the PAS domain causes structural changes which leads to kinase activation and the phosphorylation of substrates to trigger the appropriate cellular response. The PASK 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 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDCWIEDPKLGKVTLEIAILSRVE---HANIIKVLDIFENQ 1074
Cdd:cd14004     1 DYTILKEMGEGAYGQVNLAIYKSKGKEVVIKFIFKERILVDTWVRDRKLGTVPLEIHILDTLNkrsHPNIVKLLDFFEDD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 355477269 1075 GFFQLVMEKHGSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14004    81 EFYYLVMEKHGSGMDLFDFIERKPNMDEKEAKYIFRQVADA 121

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 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEdcwiedpKLGKVTLEIAILSRVEHANIIKVLDIFENQGFFQLVMEKH 1084
Cdd:cd00180     1 LGKGSFGKVYKARDKETGKKVAVKVIPKEKLKK-------LLEELLREIEILKKLNHPNIVKLYDVFETENFLYLVMEYC 73

                          90       100
                  ....*....|....*....|....*....
gi 355477269 1085 GSGlDLFAFIDRH-PRLDEPLASYIFRQV 1112
Cdd:cd00180    74 EGG-SLKDLLKENkGPLSEEEALSILRQL 101

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDcwiedpKLGKVTLEIAILSRVEHANIIKVLDIFENQGFF 1077
Cdd:cd05117     1 KYELGKVLGRGSFGVVRLAVHKKTGEEYAVKIIDKKKLKSE------DEEMLRREIEILKRLDHPNIVKLYEVFEDDKNL 74

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 355477269 1078 QLVMEKhGSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd05117    75 YLVMEL-CTGGELFDRIVKKGSFSEREAAKIMKQI 108

Protein kinase domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269   999 YSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDcwiedpKLGKVTLEIAILSRVEHANIIKVLDIFENQGFFQ 1078
Cdd:pfam00069    1 YEVLRKLGSGSFGTVYKAKHRDTGKIVAIKKIKKEKIKKK------KDKNILREIKILKKLNHPNIVRLYDAFEDKDNLY 74

                           90       100       110
                   ....*....|....*....|....*....|....
gi 355477269  1079 LVMEkHGSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:pfam00069   75 LVLE-YVEGGSLFDLLSEKGAFSEREAKFIMKQI 107

Catalytic domain of the Serine/Threonine kinases, Autophagy-related protein 1 and Unc-51-like kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes yeast ATG1 and metazoan homologs including vertebrate ULK1-3. The ATG1/ULK complex is conserved from yeast to humans and it plays a critical role in the initiation of autophagy, the intracellular system that leads to the lysosomal degradation of cellular components and their recycling into basic metabolic units. It is involved in nutrient sensing and signaling, the assembly of autophagy factors and the execution of autophagy. In metazoans, ATG1 homologs display additional functions. Unc-51 and ULKs have been implicated in neuronal and axonal development. The ATG1/ULK 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 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLedcwiedPKLGK-VTLEIAILSRVEHANIIKVLDIFENQGFFQLVMEK 1083
Cdd:cd14009     1 IGRGSFATVWKGRHKQTGEVVAIKEISRKKLN-------KKLQEnLESEIAILKSIKHPNIVRLYDVQKTEDFIYLVLEY 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 355477269 1084 HGSGlDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14009    74 CAGG-DLSQYIRKRGRLPEAVARHFMQQLASG 104

Catalytic domain of Brain-specific serine/threonine-protein kinases 1 and 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BRSK1, also called SAD-B or SAD1 (Synapses of Amphids Defective homolog 1), and BRSK2, also called SAD-A, are highly expressed in mammalian forebrain. They play important roles in establishing neuronal polarity. BRSK1/2 double knock-out mice die soon after birth, showing thin cerebral cortices due to disordered subplate layers and neurons that lack distinct axons and dendrites. BRSK1 regulates presynaptic neurotransmitter release. Its activity fluctuates during cell cysle progression and it acts as a regulator of centrosome duplication. BRSK2 is also abundant in pancreatic islets, where it is involved in the regulation of glucose-stimulated insulin secretion. The BRSK1/2 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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDcwiedPKLGKVTLEIAILSRVEHANIIKVLDIFENQGFFQLVMEkH 1084
Cdd:cd14081     9 LGKGQTGLVKLAKHCVTGQKVAIKIVNKEKLSKE-----SVLMKVEREIAIMKLIEHPNVLKLYDVYENKKYLYLVLE-Y 82

                          90       100       110
                  ....*....|....*....|....*....|.
gi 355477269 1085 GSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14081    83 VSGGELFDYLVKKGRLTEKEARKFFRQIISA 113

Catalytic domain of bacterial Serine/Threonine kinases, PknB and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes many bacterial eukaryotic-type STKs including Staphylococcus aureus PknB (also called PrkC or Stk1), Bacillus subtilis PrkC, and Mycobacterium tuberculosis Pkn proteins (PknB, PknD, PknE, PknF, PknL, and PknH), among others. S. aureus PknB is the only eukaryotic-type STK present in this species, although many microorganisms encode for several such proteins. It is important for the survival and pathogenesis of S. aureus as it is involved in the regulation of purine and pyrimidine biosynthesis, cell wall metabolism, autolysis, virulence, and antibiotic resistance. M. tuberculosis PknB is essential for growth and it acts on diverse substrates including proteins involved in peptidoglycan synthesis, cell division, transcription, stress responses, and metabolic regulation. B. subtilis PrkC is located at the inner membrane of endospores and functions to trigger spore germination. Bacterial STKs in this subfamily show varied domain architectures. The well-characterized members such as S. aureus and M. tuberculosis PknB, and B. subtilis PrkC, contain an N-terminal cytosolic kinase domain, a transmembrane (TM) segment, and mutliple C-terminal extracellular PASTA domains. The PknB 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 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVledcwiEDPKLGKVTL-EIAILSRVEHANIIKVLDIFENQGF 1076
Cdd:cd14014     1 RYRLVRLLGRGGMGEVYRARDTLLGRPVAIKVLRPELA------EDEEFRERFLrEARALARLSHPNIVRVYDVGEDDGR 74

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 355477269 1077 FQLVMEKHgSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd14014    75 PYIVMEYV-EGGSLADLLRERGPLPPREALRILAQI 109

Catalytic domain of the yeast Serine/Threonine Kinases, Rad53 and Cds1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Rad53 and Cds1 are the checkpoint kinase 2 (Chk2) homologs found in budding and fission yeast, respectively. They play a central role in the cell's response to DNA lesions to prevent genome rearrangements and maintain genome integrity. They are phosphorylated in response to DNA damage and incomplete replication, and are essential for checkpoint control. They help promote DNA repair by stalling the cell cycle prior to mitosis in the presence of DNA damage. The Rad53/Cds1 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 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLedcwIEDPKLGKVTLEIAILSRVEHANIIKVLDIFENQGFF 1077
Cdd:cd14098     1 KYQIIDRLGSGTFAEVKKAVEVETGKMRAIKQIVKRKVA----GNDKNLQLFQREINILKSLEHPGIVRLIDWYEDDQHI 76

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 355477269 1078 QLVMEkHGSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd14098    77 YLVME-YVEGGDLMDFIMAWGAIPEQHARELTKQI 110

Catalytic domain of the yeast Serine/Threonine Kinase, Kin4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Kin4 is a central component of the spindle position checkpoint (SPOC), which monitors spindle position and regulates the mitotic exit network (MEN). Kin4 associates with spindle pole bodies in mother cells to inhibit MEN signaling and delay mitosis until the anaphase nucleus is properly positioned along the mother-bud axis. Kin4 activity is regulated by both the bud neck-associated kinase Elm1 and protein phosphatase 2A. The Kin4 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 355477269  999 YSTMSPLGSGAFGFV---WTA--VDKEKNKEVVVKFIKKEKVLEDCwiedpKLGKVTLEIAILSRVEHANIIKVLDIFEN 1073
Cdd:cd14076     3 YILGRTLGEGEFGKVklgWPLpkANHRSGVQVAIKLIRRDTQQENC-----QTSKIMREINILKGLTHPNIVRLLDVLKT 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 355477269 1074 QGFFQLVMEkHGSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14076    78 KKYIGIVLE-FVSGGELFDYILARRRLKDSVACRLFAQLISG 118

Catalytic domain of the Serine/Threonine kinase, Proviral Integration Moloney virus (PIM) kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The PIM gene locus was discovered as a result of the cloning of retroviral intergration sites in murine Moloney leukemia virus, leading to the identification of PIM kinases. They are constitutively active STKs with a broad range of cellular targets and are overexpressed in many haematopoietic malignancies and solid cancers. Vertebrates contain three distinct PIM kinase genes (PIM1-3). PIM3 can inhibit apoptosis and promote cell survival and protein translation, therefore, it can enhance the proliferation of normal and cancer cells. Mice deficient with PIM3 show minimal effects, suggesting that PIM3 msy not be essential. Since its expression is enhanced in several cancers, it may make a good molecular target for cancer drugs. The PIM3 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 355477269  999 YSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEdcWiedPKLGKVT--LEIAILSRVEHA--NIIKVLDIFENQ 1074
Cdd:cd14102     2 YQVGSVLGSGGFGTVYAGSRIADGLPVAVKHVVKERVTE--W---GTLNGVMvpLEIVLLKKVGSGfrGVIKLLDWYERP 76

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 355477269 1075 GFFQLVMEKHGSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd14102    77 DGFLIVMERPEPVKDLFDFITEKGALDEDTARGFFRQV 114

Catalytic domain of the Alpha subunit of the Serine/Threonine Kinase, AMP-activated protein kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. AMPK, also called SNF1 (sucrose non-fermenting1) in yeasts and SnRK1 (SNF1-related kinase1) in plants, is a heterotrimeric enzyme composed of a catalytic alpha subunit and two regulatory subunits, beta and gamma. It is a stress-activated kinase that serves as master regulator of glucose and lipid metabolism by monitoring carbon and energy supplies, via sensing the cell's AMP:ATP ratio. In response to decreased ATP levels, it enhances energy-producing processes and inhibits energy-consuming pathways. Once activated, AMPK phosphorylates a broad range of downstream targets, with effects in carbohydrate metabolism and uptake, lipid and fatty acid biosynthesis, carbon energy storage, and inflammation, among others. Defects in energy homeostasis underlie many human diseases including Type 2 diabetes, obesity, heart disease, and cancer. As a result, AMPK has emerged as a therapeutic target in the treatment of these diseases. The AMPK 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 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKKEKvledcwIEDPKL-GKVTLEIAILSRVEHANIIKVLDIFENQGFFQLVMEk 1083
Cdd:cd14079    10 LGVGSFGKVKLAEHELTGHKVAVKILNRQK------IKSLDMeEKIRREIQILKLFRHPHIIRLYEVIETPTDIFMVME- 82

                          90       100       110
                  ....*....|....*....|....*....|..
gi 355477269 1084 HGSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14079    83 YVSGGELFDYIVQKGRLSEDEARRFFQQIISG 114

Catalytic domain of the Serine/Threonine Kinase, Death-Associated Protein Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. DAPKs mediate cell death and act as tumor suppressors. They are necessary to induce cell death and their overexpression leads to death-associated changes including membrane blebbing, cell rounding, and formation of autophagic vesicles. Vertebrates contain three subfamily members with different domain architecture, localization, and function. DAPK1 is the prototypical member of the subfamily and is also simply referred to as DAPK. DAPK2 is also called DAPK-related protein 1 (DRP-1), while DAPK3 has also been named DAP-like kinase (DLK) and zipper-interacting protein kinase (ZIPk). These proteins are ubiquitously expressed in adult tissues, are capable of cross talk with each other, and may act synergistically in regulating cell death. The DAPK 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 355477269  999 YSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVledcwiEDPKLG----KVTLEIAILSRVEHANIIKVLDIFENQ 1074
Cdd:cd14105     7 YDIGEELGSGQFAVVKKCREKSTGLEYAAKFIKKRRS------KASRRGvsreDIEREVSILRQVLHPNIITLHDVFENK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 355477269 1075 GFFQLVMEKHgSGLDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14105    81 TDVVLILELV-AGGELFDFLAEKESLSEEEATEFLKQILDG 120

Catalytic domain of Fungal Pat1-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 Schizosaccharomyces pombe Pat1 (also called Ran1), Saccharomyces cerevisiae VHS1 and KSP1, and similar fungal STKs. Pat1 blocks Mei2, an RNA-binding protein which is indispensable in the initiation of meiosis. Pat1 is inactivated and Mei2 activated, which initiates meiosis, under nutrient-deprived conditions through a signaling cascade involving Ste11. Meiosis induced by Pat1 inactivation may show different characteristics than normal meiosis including aberrant positioning of centromeres. VHS1 was identified in a screen for suppressors of cell cycle arrest at the G1/S transition, while KSP1 may be involved in regulating PRP20, which is required for mRNA export and maintenance of nuclear structure. The Pat1-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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269  998 KYSTMSPLGSGAFGFVWTAVDKEKNKEVVVKFIKK----EKVLEDcWIEDPKLGkvtlEIAILSRV-EHANIIKVLDIFE 1072
Cdd:cd13993     1 RYQLISPIGEGAYGVVYLAVDLRTGRKYAIKCLYKsgpnSKDGND-FQKLPQLR----EIDLHRRVsRHPNIITLHDVFE 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 355477269 1073 NQGFFQLVMEkHGSGLDLFAFI--DRHPRLDEPLASYIFRQV 1112
Cdd:cd13993    76 TEVAIYIVLE-YCPNGDLFEAIteNRIYVGKTELIKNVFLQL 116

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKK-------EKVLEDCWIEDPkLGKVTLEIAILSRVEHANIIK---VLDIFENQ 1074
Cdd:cd14008     1 LGRGSFGKVKLALDTETGQLYAIKIFNKsrlrkrrEGKNDRGKIKNA-LDDVRREIAIMKKLDHPNIVRlyeVIDDPESD 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 355477269 1075 GFFqLVME--KHGSGLDLFAFiDRHPRLDEPLASYIFRQVRAG 1115
Cdd:cd14008    80 KLY-LVLEycEGGPVMELDSG-DRVPPLPEETARKYFRDLVLG 120

Catalytic domain of the Serine/Threonine kinase, Proviral Integration Moloney virus (PIM) kinase 2; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The PIM gene locus was discovered as a result of the cloning of retroviral intergration sites in murine Moloney leukemia virus, leading to the identification of PIM kinases. They are constitutively active STKs with a broad range of cellular targets and are overexpressed in many haematopoietic malignancies and solid cancers. Vertebrates contain three distinct PIM kinase genes (PIM1-3); each gene may result in mutliple protein isoforms. There are three PIM2 isoforms resulting from alternative translation initiation sites. PIM2 is highly expressed in leukemia and lymphomas and has been shown to promote the survival and proliferation of tumor cells. The PIM2 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 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEdcWIEDPKLGKVTLEIAILSRV----EHANIIKVLDIFENQGFFQLV 1080
Cdd:cd14101     8 LGKGGFGTVYAGHRISDGLQVAIKQISRNRVQQ--WSKLPGVNPVPNEVALLQSVgggpGHRGVIRLLDWFEIPEGFLLV 85

                          90       100       110
                  ....*....|....*....|....*....|..
gi 355477269 1081 MEKHGSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd14101    86 LERPQHCQDLFDYITERGALDESLARRFFKQV 117

Catalytic domain of the Serine/Threonine kinase, Unc-51-like kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The ATG1/ULK complex is conserved from yeast to humans and it plays a critical role in the initiation of autophagy, the intracellular system that leads to the lysosomal degradation of cellular components and their recycling into basic metabolic units. ULK3 mRNA is up-regulated in fibroblasts after Ras-induced senescence, and its overexpression induces both autophagy and senescence in a fibroblast cell line. ULK3, through its kinase activity, positively regulates Gli proteins, mediators of the Sonic hedgehog (Shh) signaling pathway that is implicated in tissue homeostasis maintenance and neurogenesis. It is inhibited by binding to Suppressor of Fused (Sufu). The ULK3 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 355477269 1005 LGSGAFGFVWTAVDKEKNKEVV-VKFIKKEKvledcwiedpkLGKVT-----LEIAILSRVEHANIIKVLDIFENQGFFQ 1078
Cdd:cd14121     3 LGSGTYATVYKAYRKSGAREVVaVKCVSKSS-----------LNKAStenllTEIELLKKLKHPHIVELKDFQWDEEHIY 71

                          90       100       110
                  ....*....|....*....|....*....|...
gi 355477269 1079 LVMEkHGSGLDLFAFIDRHPRLDEPLASYIFRQ 1111
Cdd:cd14121    72 LIME-YCSGGDLSRFIRSRRTLPESTVRRFLQQ 103

Catalytic domain of the Serine/Threonine kinase, Calcium/calmodulin-dependent protein kinase Type I gamma; 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. The CaMK family includes CaMKI, CaMKII, CaMKIV, and CaMK kinase (CaMKK). In vertebrates, there are four CaMKI proteins encoded by different genes (alpha, beta, gamma, and delta), each producing at least one variant. CaMKs contain an N-terminal catalytic domain and a C-terminal regulatory domain that harbors a CaM binding site. 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. In addition, they may be involved in osteoclast differentiation and bone resorption. The CaMKI-gamma subfamily is part of a larger superfamily that includes the catalytic domains of other protein kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269 1002 MSPLGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDCWIEDpklgkvtlEIAILSRVEHANIIKVLDIFENQGFFQLVM 1081
Cdd:cd14166     8 MEVLGSGAFSEVYLVKQRSTGKLYALKCIKKSPLSRDSSLEN--------EIAVLKRIKHENIVTLEDIYESTTHYYLVM 79

                          90       100       110
                  ....*....|....*....|....*....|.
gi 355477269 1082 EKHgSGLDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd14166    80 QLV-SGGELFDRILERGVYTEKDASRVINQV 109

Catalytic domain of testis-specific serine/threonine kinases and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TSSK proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. There are five mammalian TSSK proteins which show differences in their localization and timing of expression. TSSK1 and TSSK2 are expressed specifically in meiotic and postmeiotic spermatogenic cells, respectively. TSSK3 has been reported to be expressed in the interstitial Leydig cells of adult testis. TSSK4, also called TSSK5, is expressed in testis from haploid round spermatids to mature spermatozoa. TSSK6, also called SSTK, is expressed at the head of elongated sperm. TSSK1/TSSK2 double knock-out and TSSK6 null mice are sterile without manifesting other defects, making these kinases viable targets for male contraception. The TSSK-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 355477269 1005 LGSGAFGFVWTA--VDKEKNKEVVVKFIKKEKVLEDcWIED--PKlgkvtlEIAILSRVEHANIIKVLDIFENQGFFQLV 1080
Cdd:cd14080     8 IGEGSYSKVKLAeyTKSGLKEKVACKIIDKKKAPKD-FLEKflPR------ELEILRKLRHPNIIQVYSIFERGSKVFIF 80

                          90       100       110
                  ....*....|....*....|....*....|..
gi 355477269 1081 MEKHGSGlDLFAFIDRHPRLDEPLASYIFRQV 1112
Cdd:cd14080    81 MEYAEHG-DLLEYIQKRGALSESQARIWFRQL 111

cyclin-dependent protein kinase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355477269 1005 LGSGAFGFVWTAVDKEKNKEVVVKFIKKEKVLEDCWIEDPKLGKVTL------EIAILSRVEHANIIKVLDIFENQGFFQ 1078
Cdd:PTZ00024   17 LGEGTYGKVEKAYDTLTGKIVAIKKVKIIEISNDVTKDRQLVGMCGIhfttlrELKIMNEIKHENIMGLVDVYVEGDFIN 96

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 355477269 1079 LVMEKHGSglDLFAFIDRHPRLDEPLASYIFRQVRAG 1115
Cdd:PTZ00024   97 LVMDIMAS--DLKKVVDRKIRLTESQVKCILLQILNG 131