Caspase activation and recruitment domain of Receptor Interacting Protein 2; Caspase activation and recruitment domain (CARD) of Receptor Interacting Protein 2 (RIP2/RIPK2/RICK/CARDIAK/CARD3). RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains. RIP2 harbors a C-terminal CARD domain and functions as an effector kinase downstream of the pattern recognition receptors from the Nod-like (NLR)-family, NOD1 and NOD2, which recognizes bacterial peptidoglycans released upon infection. This cascade is implicated in inflammatory immune responses and the clearance of intracellular pathogens. RIP2 associates with NOD1 and NOD2 via CARD-CARD interactions. In general, CARDs are death domains (DDs) found associated with caspases. They are known to be important in the signaling pathways for apoptosis, inflammation, and host-defense mechanisms. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including PYRIN and DED (Death Effector Domain). They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763 267 QWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGL 346
Cdd:cd08786    1 QWIASKREEIVSQMTEACLNQSLDALLSRQLLMREDYELISTKPTRTSKVRQLLDTCDCQGEEFARVVVQKLKDNKQMGL 80

                 ....*..
gi 767953763 347 QPYPEIL 353
Cdd:cd08786   81 QPYPDII 87

Caspase activation and recruitment domain of Receptor Interacting Protein 2; Caspase activation and recruitment domain (CARD) of Receptor Interacting Protein 2 (RIP2/RIPK2/RICK/CARDIAK/CARD3). RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains. RIP2 harbors a C-terminal CARD domain and functions as an effector kinase downstream of the pattern recognition receptors from the Nod-like (NLR)-family, NOD1 and NOD2, which recognizes bacterial peptidoglycans released upon infection. This cascade is implicated in inflammatory immune responses and the clearance of intracellular pathogens. RIP2 associates with NOD1 and NOD2 via CARD-CARD interactions. In general, CARDs are death domains (DDs) found associated with caspases. They are known to be important in the signaling pathways for apoptosis, inflammation, and host-defense mechanisms. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including PYRIN and DED (Death Effector Domain). They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763 267 QWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGL 346
Cdd:cd08786    1 QWIASKREEIVSQMTEACLNQSLDALLSRQLLMREDYELISTKPTRTSKVRQLLDTCDCQGEEFARVVVQKLKDNKQMGL 80

                 ....*..
gi 767953763 347 QPYPEIL 353
Cdd:cd08786   81 QPYPDII 87

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763    21 YMPPENYepgQKSRASIKHDIYSYAVITWEVLSR-KQPFEDVTNpLQIMYSVSQGHRPvineeslpyDIPHR--ARMISL 97
Cdd:smart00219 169 WMAPESL---KEGKFTSKSDVWSFGVLLWEIFTLgEQPYPGMSN-EEVLEYLKNGYRL---------PQPPNcpPELYDL 235

                           90       100
                   ....*....|....*....|..
gi 767953763    98 IESGWAQNPDERPSFLKCLIEL 119
Cdd:smart00219 236 MLQCWAEDPEDRPTFSELVEIL 257

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  17 GTIIYMPPENYEPGQKSRASikhDIYSYAVITWEVLSRKQPFeDVTNPLQIMYSVSqgHRPVINEESLPYDIPHR----- 91
Cdd:COG0515  170 GTPGYMAPEQARGEPVDPRS---DVYSLGVTLYELLTGRPPF-DGDSPAELLRAHL--REPPPPPSELRPDLPPAldaiv 243

                         90       100
                 ....*....|....*....|
gi 767953763  92 ARMIsliesgwAQNPDERPS 111
Cdd:COG0515  244 LRAL-------AKDPEERYQ 256

Caspase activation and recruitment domain of Receptor Interacting Protein 2; Caspase activation and recruitment domain (CARD) of Receptor Interacting Protein 2 (RIP2/RIPK2/RICK/CARDIAK/CARD3). RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains. RIP2 harbors a C-terminal CARD domain and functions as an effector kinase downstream of the pattern recognition receptors from the Nod-like (NLR)-family, NOD1 and NOD2, which recognizes bacterial peptidoglycans released upon infection. This cascade is implicated in inflammatory immune responses and the clearance of intracellular pathogens. RIP2 associates with NOD1 and NOD2 via CARD-CARD interactions. In general, CARDs are death domains (DDs) found associated with caspases. They are known to be important in the signaling pathways for apoptosis, inflammation, and host-defense mechanisms. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including PYRIN and DED (Death Effector Domain). They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763 267 QWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGL 346
Cdd:cd08786    1 QWIASKREEIVSQMTEACLNQSLDALLSRQLLMREDYELISTKPTRTSKVRQLLDTCDCQGEEFARVVVQKLKDNKQMGL 80

                 ....*..
gi 767953763 347 QPYPEIL 353
Cdd:cd08786   81 QPYPDII 87

Catalytic domain of the Serine/Threonine kinases, Receptor Interacting Protein 4 and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of RIP4, ankyrin (ANK) repeat and kinase domain containing 1 (ANKK1), and similar proteins, all of which harbor C-terminal ANK repeats. RIP4, also called Protein Kinase C-associated kinase (PKK), regulates keratinocyte differentiation and cutaneous inflammation. It activates NF-kappaB and is important in the survival of diffuse large B-cell lymphoma cells. The ANKK1 protein, also called PKK2, has not been studied extensively. The ANKK1 gene, located less than 10kb downstream of the D2 dopamine receptor (DRD2) locus, is altered in the Taq1 A1 polymorphism, which is related to a reduced DRD2 binding affinity and consequently, to mental disorders. The RIP4-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 767953763  17 GTIIYMPPENYEpgQKSRAS-IKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVIneESLPYDIPHRA-RM 94
Cdd:cd14025  159 GTIAYLPPERFK--EKNRCPdTKHDVYSFAIVIWGILTQKKPFAGENNILHIMVKVVKGHRPSL--SPIPRQRPSECqQM 234

                         90       100
                 ....*....|....*....|....*....
gi 767953763  95 ISLIESGWAQNPDERPSFLKCLIELEPVL 123
Cdd:cd14025  235 ICLMKRCWDQDPRKRPTFQDITSETENLL 263

Catalytic domain of the Serine/Threonine Kinase, Transforming Growth Factor beta Activated Kinase-1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TAK1 is also known as mitogen-activated protein kinase kinase kinase 7 (MAPKKK7 or MAP3K7), TAK, or MEKK7. As a MAPKKK, it is an important mediator of cellular responses to extracellular signals. It regulates both the c-Jun N-terminal kinase and p38 MAPK cascades by activating the MAPK kinases, MKK4 and MKK3/6. In addition, TAK1 plays diverse roles in immunity and development, in different biological contexts, through many signaling pathways including TGFbeta/BMP, Wnt/Fz, and NF-kB. It is also implicated in the activation of the tumor suppressor kinase, LKB1. The TAK1 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 767953763  17 GTIIYMPPENYEpgqKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNP-LQIMYSVSQGHRPVInEESLPYDIPhrarmi 95
Cdd:cd14058  152 GSAAWMAPEVFE---GSKYSEKCDVFSWGIILWEVITRRKPFDHIGGPaFRIMWAVHNGERPPL-IKNCPKPIE------ 221

                         90
                 ....*....|....*..
gi 767953763  96 SLIESGWAQNPDERPSF 112
Cdd:cd14058  222 SLMTRCWSKDPEKRPSM 238

Caspase recruitment domain; Motif contained in proteins involved in apoptotic signaling. Predicted to possess a DEATH (pfam00531) domain-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  266 QQWIQSKREDIVNQMTeaCLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKdNKQMG 345
Cdd:pfam00619   1 RKLLKKNRVALVERLG--TLDGLLDYLLEKNVLTEEEEEKIKANPTRLDKARELLDLVLKKGPKACQIFLEALK-EGDPD 77

                  ....*...
gi 767953763  346 LQPYPEIL 353
Cdd:pfam00619  78 LASDLEGL 85

Catalytic domain of the Serine/Threonine kinase, Oocyte maturation factor Mos; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Mos (or c-Mos) is a germ-cell specific kinase that plays roles in both the release of primary arrest and the induction of secondary arrest in oocytes. It is expressed towards the end of meiosis I and is quickly degraded upon fertilization. It is a component of the cytostatic factor (CSF), which is responsible for metaphase II arrest. In addition, Mos activates a phoshorylation cascade that leads to the activation of the p34 subunit of MPF (mitosis-promoting factor or maturation promoting factor), a cyclin-dependent kinase that is responsible for the release of primary arrest in meiosis I. The Mos 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 767953763  16 GGTIIYMPPE---NYEPGQKSrasikhDIYSYAVITWEVLSRKQPFEDVtNPLQIMYSVSQGHRP--VINEESLPYDiph 90
Cdd:cd13979  167 GGTYTYRAPEllkGERVTPKA------DIYSFGITLWQMLTRELPYAGL-RQHVLYAVVAKDLRPdlSGLEDSEFGQ--- 236

                         90       100       110
                 ....*....|....*....|....*....|....
gi 767953763  91 RARmiSLIESGWAQNPDERPSflkCLIELEPVLR 124
Cdd:cd13979  237 RLR--SLISRCWSAQPAERPN---ADESLLKSLE 265

Catalytic domain of the Dual-specificity protein kinase, TNNI3-interacting kinase; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine as well as tyrosine residues on protein substrates. TNNI3K, also called cardiac ankyrin repeat kinase (CARK), is a cardiac-specific troponin I-interacting kinase that promotes cardiac myogenesis, improves cardiac performance, and protects the myocardium from ischemic injury. It contains N-terminal ankyrin repeats, a catalytic kinase domain, and a C-terminal serine-rich domain. TNNI3K exerts a disease-accelerating effect on cardiac dysfunction and reduced survival in mouse models of cardiomyopathy. The TNNI3K subfamily is part of a larger superfamily that includes the catalytic domains of other protein serine/threonine PKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  17 GTIIYMPPENYEpgQKSRASIKHDIYSYAVITWEVLSRKQPFEDVtNPLQIMYSVSQGH-RPVIneeslPYDIPhrARMI 95
Cdd:cd14064  158 GNLRWMAPEVFT--QCTRYSIKADVFSYALCLWELLTGEIPFAHL-KPAAAAADMAYHHiRPPI-----GYSIP--KPIS 227

                         90       100
                 ....*....|....*....|....*.
gi 767953763  96 SLIESGWAQNPDERPSFLKCLIELEP 121
Cdd:cd14064  228 SLLMRGWNAEPESRPSFVEIVALLEP 253

Catalytic domain of the Serine/Threonine Kinase, Mixed lineage kinase-Like mitogen-activated protein Triple Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLTK, also called zipper sterile-alpha-motif kinase (ZAK), contains a catalytic kinase domain and a leucine zipper. There are two alternatively-spliced variants, MLTK-alpha and MLTK-beta. MLTK-alpha contains a sterile-alpha-motif (SAM) at the C-terminus. MLTK regulates the c-Jun N-terminal kinase, extracellular signal-regulated kinase, p38 MAPK, and NF-kB pathways. ZAK is the MAP3K involved in the signaling cascade that leads to the ribotoxic stress response initiated by cellular damage due to Shiga toxins and ricin. It may also play a role in cell transformation and cancer development. 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.The MLTK 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 767953763  17 GTIIYMPPENYepgQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNpLQIMY-SVSQGHRPVInEESLPydiphrARMI 95
Cdd:cd14060  147 GTFPWMAPEVI---QSLPVSETCDTYSYGVVLWEMLTREVPFKGLEG-LQVAWlVVEKNERPTI-PSSCP------RSFA 215

                         90       100
                 ....*....|....*....|....*
gi 767953763  96 SLIESGWAQNPDERPSFLKCLIELE 120
Cdd:cd14060  216 ELMRRCWEADVKERPSFKQIIGILE 240

Catalytic domain of the Serine/Threonine Kinases, Transforming Growth Factor beta family Type I Receptors; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of type I receptors for the TGFbeta family of secreted signaling molecules including TGFbeta, bone morphogenetic proteins, activins, growth and differentiation factors, and anti-Mullerian hormone, among others. These receptors contain an extracellular domain that binds ligands, a single transmembrane (TM) region, and a cytoplasmic catalytic kinase domain. Type I receptors are low-affinity receptors that bind ligands only after they are recruited by the ligand/type II high-affinity receptor complex. Following activation through trans-phosphorylation by type II receptors, they start intracellular signaling to the nucleus by phosphorylating SMAD proteins. Type I receptors contain an additional domain located between the TM and kinase domains called the GS domain, which contains the activating phosphorylation site and confers preference for specific SMAD proteins. They are inhibited by the immunophilin FKBP12, which is thought to control leaky signaling caused by receptor oligomerization in the absence of ligand. The TGFbR-I 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 767953763  14 PEGGTIIYMPPE--NYEPGQKSRASIKH-DIYSYAVITWEVLSR----------KQPFEDVTNP---LQIMYSV--SQGH 75
Cdd:cd14056  163 PRVGTKRYMAPEvlDDSINPKSFESFKMaDIYSFGLVLWEIARRceiggiaeeyQLPYFGMVPSdpsFEEMRKVvcVEKL 242

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 767953763  76 RPVINEESlpYDIPHRARMISLIESGWAQNPDERPSFLKCLIEL 119
Cdd:cd14056  243 RPPIPNRW--KSDPVLRSMVKLMQECWSENPHARLTALRVKKTL 284

Pseudokinase domain of membrane Guanylate Cyclase receptors; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. Membrane (or particulate) GCs consist of an extracellular ligand-binding domain, a single transmembrane region, and an intracellular tail that contains a PK-like domain, an amphiphatic region and a catalytic GC domain that catalyzes the conversion of GTP into cGMP and pyrophosphate. Membrane GCs act as receptors that transduce an extracellular signal to the intracellular production of cGMP, which has been implicated in many processes including cell proliferation, phototransduction, and muscle contractility, through its downstream effectors such as PKG. The PK-like domain of GCs lack a critical aspartate involved in ATP binding and does not exhibit kinase activity. It functions as a negative regulator of the catalytic GC domain and may also act as a docking site for interacting proteins such as GC-activating proteins. The GC subfamily is part of a larger superfamily that includes the catalytic domains of protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  20 IYMPPE---NYEPGQksRASIKHDIYSYAVITWEVLSRKQPFEDVTnPLQIMYSVSQGHRPVINEESLPYDIPHRARMIS 96
Cdd:cd13992  166 LWTAPEllrGSLLEV--RGTQKGDVYSFAIILYEILFRSDPFALER-EVAIVEKVISGGNKPFRPELAVLLDEFPPRLVL 242

                         90
                 ....*....|....*.
gi 767953763  97 LIESGWAQNPDERPSF 112
Cdd:cd13992  243 LVKQCWAENPEKRPSF 258

Catalytic domain of Tec-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The Tec-like subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases form the second largest subfamily of nonreceptor PTKs and are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. Tec kinases play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. Mutations in Btk cause the severe B-cell immunodeficiency, X-linked agammaglobulinaemia (XLA). The Tec-like 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 767953763  19 IIYMPPENYEpgqKSRASIKHDIYSYAVITWEVLSR-KQPFEDVTNpLQIMYSVSQGHRpvineeslpYDIPHRARM--I 95
Cdd:cd05059  165 VKWSPPEVFM---YSKFSSKSDVWSFGVLMWEVFSEgKMPYERFSN-SEVVEHISQGYR---------LYRPHLAPTevY 231

                         90       100
                 ....*....|....*....|.
gi 767953763  96 SLIESGWAQNPDERPSFLKCL 116
Cdd:cd05059  232 TIMYSCWHEKPEERPTFKILL 252

Catalytic domain of the Serine/Threonine Kinase, Mixed Lineage Kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLK4 is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates 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. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. Mammals have four MLKs, mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation.The MLK4 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 767953763  16 GGTIIYMPPENYEPGQKSRASikhDIYSYAVITWEVLSRKQPFEDVtNPLQIMYSVSqghrpvINEESLPYDIPHRARMI 95
Cdd:cd14146  172 AGTYAWMAPEVIKSSLFSKGS---DIWSYGVLLWELLTGEVPYRGI-DGLAVAYGVA------VNKLTLPIPSTCPEPFA 241

                         90       100
                 ....*....|....*....|....*..
gi 767953763  96 SLIESGWAQNPDERPSFLKCLIELEPV 122
Cdd:cd14146  242 KLMKECWEQDPHIRPSFALILEQLTAI 268

Pseudokinase domain of the Protein Tyrosine Kinase, Colon Carcinoma Kinase 4; CCK4, also called protein tyrosine kinase 7 (PTK7), is an orphan receptor PTK (RTK) containing an extracellular region with seven immunoglobulin domains, a transmembrane segment, and an intracellular inactive pseudokinase domain, which shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. Studies in mice reveal that CCK4 is essential for neural development. Mouse embryos containing a truncated CCK4 die perinatally and display craniorachischisis, a severe form of neural tube defect. The mechanism of action of the CCK4 pseudokinase is still unknown. Other pseudokinases such as HER3 rely on the activity of partner RTKs. The CCK4 subfamily is part of a larger superfamily that includes other pseudokinases and the catalytic domains of active kinases including PTKs, protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  21 YMPPENYepgQKSRASIKHDIYSYAVITWEVLSR-KQPFEDVTNPlqimySVSQGhrpvINEESLPYDIPHR--ARMISL 97
Cdd:cd05046  184 WLAPEAV---QEDDFSTKSDVWSFGVLMWEVFTQgELPFYGLSDE-----EVLNR----LQAGKLELPVPEGcpSRLYKL 251

                         90       100
                 ....*....|....*....|...
gi 767953763  98 IESGWAQNPDERPSFLKCLIELE 120
Cdd:cd05046  252 MTRCWAVNPKDRPSFSELVSALG 274

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763    17 GTIIYMPPE--NYEP-GQKSrasikhDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESlpyDIPHRAR 93
Cdd:smart00220 158 GTPEYMAPEvlLGKGyGKAV------DIWSLGVILYELLTGKPPFPGDDQLLELFKKIGKPKPPFPPPEW---DISPEAK 228

                           90       100
                   ....*....|....*....|...
gi 767953763    94 miSLIESGWAQNPDERPSFLKCL 116
Cdd:smart00220 229 --DLIRKLLVKDPEKRLTAEEAL 249

Catalytic domain of the Protein Tyrosine Kinases, Bruton's tyrosine kinase and Bone marrow kinase on the X chromosome; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Btk and Bmx (also named Etk) are members of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, Btk contains the Tec homology (TH) domain with proline-rich and zinc-binding regions. Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor, leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans. Bmx is primarily expressed in bone marrow and the arterial endothelium, and plays an important role in ischemia-induced angiogenesis. It facilitates arterial growth, capillary formation, vessel maturation, and bone marrow-derived endothelial progenitor cell mobilization. The Btk/Bmx 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 767953763  23 PPENYepgQKSRASIKHDIYSYAVITWEVLSR-KQPFEDVTNPlQIMYSVSQGHRPVineeslpydIPHRA--RMISLIE 99
Cdd:cd05113  169 PPEVL---MYSKFSSKSDVWAFGVLMWEVYSLgKMPYERFTNS-ETVEHVSQGLRLY---------RPHLAseKVYTIMY 235

                         90       100
                 ....*....|....*....|.
gi 767953763 100 SGWAQNPDERPSFLKCLIELE 120
Cdd:cd05113  236 SCWHEKADERPTFKILLSNIL 256

Catalytic domain of the Serine/Threonine Kinase, B-Raf (Rapidly Accelerated Fibrosarcoma) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. B-Raf activates ERK with the strongest magnitude, compared with other Raf kinases. Mice embryos deficient in B-Raf die around midgestation due to vascular hemorrhage caused by apoptotic endothelial cells. Mutations in B-Raf have been implicated in initiating tumorigenesis and tumor progression, and are found in malignant cutaneous melanoma, papillary thyroid cancer, as well as in ovarian and colorectal carcinomas. Most oncogenic B-Raf mutations are located at the activation loop of the kinase and surrounding regions; the V600E mutation accounts for around 90% of oncogenic mutations. The V600E mutant constitutively activates MEK, resulting in sustained activation of ERK. B-Raf is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates 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. They function in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. The B-Raf 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 767953763  17 GTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGH-RPVINEesLPYDIPhrARMI 95
Cdd:cd14151  168 GSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYlSPDLSK--VRSNCP--KAMK 243

                         90       100       110
                 ....*....|....*....|....*....|.
gi 767953763  96 SLIESGWAQNPDERPSFLKCLIELEPVLRTF 126
Cdd:cd14151  244 RLMAECLKKKRDERPLFPQILASIELLARSL 274

Catalytic domain of the Protein Tyrosine Kinase, Insulin Receptor; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. InsR is a receptor PTK (RTK) that is composed of two alphabeta heterodimers. Binding of the insulin ligand to the extracellular alpha subunit activates the intracellular tyr kinase domain of the transmembrane beta subunit. Receptor activation leads to autophosphorylation, stimulating downstream kinase activities, which initiate signaling cascades and biological function. InsR signaling plays an important role in many cellular processes including glucose homeostasis, glycogen synthesis, lipid and protein metabolism, ion and amino acid transport, cell cycle and proliferation, cell differentiation, gene transcription, and nitric oxide synthesis. Insulin resistance, caused by abnormalities in InsR signaling, has been described in diabetes, hypertension, cardiovascular disease, metabolic syndrome, heart failure, and female infertility. The InsR 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 767953763  21 YMPPENYEPGQKSRASikhDIYSYAVITWEVLS-RKQPFEDVTNPLQIMYSVSQGH--RPvineESLPydiphrARMISL 97
Cdd:cd05061  187 WMAPESLKDGVFTTSS---DMWSFGVVLWEITSlAEQPYQGLSNEQVLKFVMDGGYldQP----DNCP------ERVTDL 253

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 767953763  98 IESGWAQNPDERPSFLKCLIELEPVLR-TFEEITF 131
Cdd:cd05061  254 MRMCWQFNPKMRPTFLEIVNLLKDDLHpSFPEVSF 288

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 767953763  16 GGTIIYMPPENYEPGQKSRASikhDIYSYAVITWEVLSRKQPFEDVTnPLQIMYsvSQGHRPVINEESLPYDIPhrARMI 95
Cdd:cd14014  162 LGTPAYMAPEQARGGPVDPRS---DIYSLGVVLYELLTGRPPFDGDS-PAAVLA--KHLQEAPPPPSPLNPDVP--PALD 233

                         90
                 ....*....|....*.
gi 767953763  96 SLIESGWAQNPDERPS 111
Cdd:cd14014  234 AIILRALAKDPEERPQ 249

Pseudokinase domain of Kinase Suppressor of Ras; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. KSR is a scaffold protein that functions downstream of Ras and upstream of Raf in the Extracellular signal-Regulated Kinase (ERK) pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. KSR proteins regulate the assembly and activation of the Raf/MEK/ERK module upon Ras activation at the membrane by direct association of its components. They are widely regarded as pseudokinases, but there is some debate in this designation as a few groups have reported detecting kinase catalytic activity for KSRs, specifically KSR1. Vertebrates contain two KSR proteins, KSR1 and KSR2. The KSR 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 767953763  13 APEggTIIYMPPENYEPGQK--SRASikhDIYSYAVITWEVLSRKQPFEDvTNPLQIMYSVSQGHRPVINEESLPYDIPh 90
Cdd:cd14063  169 APE--IIRALSPDLDFEESLpfTKAS---DVYAFGTVWYELLAGRWPFKE-QPAESIIWQVGCGKKQSLSQLDIGREVK- 241

                         90       100
                 ....*....|....*....|..
gi 767953763  91 rarmiSLIESGWAQNPDERPSF 112
Cdd:cd14063  242 -----DILMQCWAYDPEKRPTF 258

Catalytic domain of the Protein Tyrosine Kinase, Axl; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Axl is widely expressed in a variety of organs and cells including epithelial, mesenchymal, hematopoietic, as well as non-transformed cells. It is important in many cellular functions such as survival, anti-apoptosis, proliferation, migration, and adhesion. Axl was originally isolated from patients with chronic myelogenous leukemia and a chronic myeloproliferative disorder. It is overexpressed in many human cancers including colon, squamous cell, thyroid, breast, and lung carcinomas. Axl is a member of the TAM subfamily, composed of receptor PTKs (RTKs) containing an extracellular ligand-binding region with two immunoglobulin-like domains followed by two fibronectin type III repeats, a transmembrane segment, and an intracellular catalytic domain. Binding to its ligands, Gas6 and protein S, leads to receptor dimerization, autophosphorylation, activation, and intracellular signaling. The Axl 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 767953763  36 SIKHDIYSYAVITWEVLSRKQ-PFEDVTNPlQIMYSVSQGHRpvineesLPYDIPHRARMISLIESGWAQNPDERPSFLK 114
Cdd:cd05075  193 TTKSDVWSFGVTMWEIATRGQtPYPGVENS-EIYDYLRQGNR-------LKQPPDCLDGLYELMSSCWLLNPKDRPSFET 264

                         90
                 ....*....|..
gi 767953763 115 CLIELEPVLRTF 126
Cdd:cd05075  265 LRCELEKILKDL 276

Pseudokinase domain of the membrane Guanylate Cyclase receptors, GC-A and GC-B; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity and/or ATP binding. GC-A binds and is activated by the atrial and B-type natriuretic peptides, ANP and BNP, which are important in blood pressure regulation and cardiac pathophysiology. GC-B binds the C-type natriuretic peptide, CNP, which is a potent vasorelaxant and functions in vascular remodeling and bone growth regulation. Membrane (or particulate) GCs consist of an extracellular ligand-binding domain, a single transmembrane region, and an intracellular tail that contains a PK-like domain, an amphiphatic region and a catalytic GC domain that catalyzes the conversion of GTP into cGMP and pyrophosphate. Membrane GCs act as receptors that transduce an extracellular signal to the intracellular production of cGMP, which has been implicated in many processes including cell proliferation, phototransduction, and muscle contractility, through its downstream effectors such as PKG. The PK-like domain of GCs functions as a negative regulator of the catalytic GC domain and may also act as a docking site for interacting proteins such as GC-activating proteins. The GC-A/B subfamily is part of a larger superfamily that includes the catalytic domains of protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  29 PGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQ----IMYSVSQGH----RPVINEESLPYDiphrarMISLIES 100
Cdd:cd14042  181 PNPPPPGTQKGDVYSFGIILQEIATRQGPFYEEGPDLSpkeiIKKKVRNGEkppfRPSLDELECPDE------VLSLMQR 254

                         90
                 ....*....|..
gi 767953763 101 GWAQNPDERPSF 112
Cdd:cd14042  255 CWAEDPEERPDF 266

NIMA-related protein kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  17 GTIIYMPPENYEpgqKSRASIKHDIYSYAVITWEVLSRKQPFEdvtNPLQ--IMYSVSQGHRPvineeslPYDIPHRARM 94
Cdd:PTZ00267 233 GTPYYLAPELWE---RKRYSKKADMWSLGVILYELLTLHRPFK---GPSQreIMQQVLYGKYD-------PFPCPVSSGM 299

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 767953763  95 ISLIESGWAQNPDERPSFLKCLIE--LEPVLRTFEEI 129
Cdd:PTZ00267 300 KALLDPLLSKNPALRPTTQQLLHTefLKYVANLFQDI 336

Catalytic domain of the Serine/Threonine Kinase, C-Raf (Rapidly Accelerated Fibrosarcoma) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. C-Raf, also known as Raf-1 or c-Raf-1, is ubiquitously expressed and was the first Raf identified. It was characterized as the acquired oncogene from an acutely transforming murine sarcoma virus (3611-MSV) and the transforming agent from the avian retrovirus MH2. C-Raf-deficient mice embryos die around midgestation with increased apoptosis of embryonic tissues, especially in the fetal liver. One of the main functions of C-Raf is restricting caspase activation to promote survival in response to specific stimuli such as Fas stimulation, macrophage apoptosis, and erythroid differentiation. C-Raf is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates 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. It functions in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. The C-Raf 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 767953763  17 GTIIYMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHrpVINEESLPYDIPHRArMIS 96
Cdd:cd14149  172 GSILWMAPEVIRMQDNNPFSFQSDVYSYGIVLYELMTGELPYSHINNRDQIIFMVGRGY--ASPDLSKLYKNCPKA-MKR 248

                         90       100       110
                 ....*....|....*....|....*....|...
gi 767953763  97 LIESGWAQNPDERPSFLKCLIELEPVLRTFEEI 129
Cdd:cd14149  249 LVADCIKKVKEERPLFPQILSSIELLQHSLPKI 281

Catalytic domain of the Protein Tyrosine Kinases, Met and Ron; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Met and Ron are receptor PTKs (RTKs) composed of an alpha-beta heterodimer. The extracellular alpha chain is disulfide linked to the beta chain, which contains an extracellular ligand-binding region with a sema domain, a PSI domain and four IPT repeats, a transmembrane segment, and an intracellular catalytic domain. Binding to their ligands leads to receptor dimerization, autophosphorylation, activation, and intracellular signaling. Met binds to the ligand, hepatocyte growth factor/scatter factor (HGF/SF), and is also called the HGF receptor. HGF/Met signaling plays a role in growth, transformation, cell motility, invasion, metastasis, angiogenesis, wound healing, and tissue regeneration. Aberrant expression of Met through mutations or gene amplification is associated with many human cancers including hereditary papillary renal and gastric carcinomas. The ligand for Ron is macrophage stimulating protein (MSP). Ron signaling is important in regulating cell motility, adhesion, proliferation, and apoptosis. Aberrant Ron expression is implicated in tumorigenesis and metastasis. The Met/Ron 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 767953763  28 EPGQKSRASIKHDIYSYAVITWEVLSR-KQPFEDVtNPLQIMYSVSQGHRpVINEESLPydiphrARMISLIESGWAQNP 106
Cdd:cd05058  172 ESLQTQKFTTKSDVWSFGVLLWELMTRgAPPYPDV-DSFDITVYLLQGRR-LLQPEYCP------DPLYEVMLSCWHPKP 243

                         90
                 ....*....|....*....
gi 767953763 107 DERPSFLKCLIELEPVLRT 125
Cdd:cd05058  244 EMRPTFSELVSRISQIFST 262

Pseudokinase domain of Integrin Linked Kinase; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. ILK contains N-terminal ankyrin repeats, a Pleckstrin Homology (PH) domain, and a C-terminal pseudokinase domain. It is a component of the IPP (ILK/PINCH/Parvin) complex that couples beta integrins to the actin cytoskeleton, and plays important roles in cell adhesion, spreading, invasion, and migration. ILK was initially thought to be an active kinase despite the lack of key conserved residues because of in vitro studies showing that it can phosphorylate certain protein substrates. However, in vivo experiments in Caenorhabditis elegans, Drosophila melanogaster, and mice (ILK-null and knock-in) proved that ILK is not an active kinase. In addition to actin cytoskeleton regulation, ILK also influences the microtubule network and mitotic spindle orientation. The pseudokinase domain of ILK binds several adaptor proteins including the parvins and paxillin. The ILK subfamily is part of a larger superfamily that includes the catalytic domains of protein serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767953763  21 YMPPENYEPGQKSRASIKHDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINeeslPYDIPHRARMISLIES 100
Cdd:cd14057  157 WMAPEALQKKPEDINRRSADMWSFAILLWELVTREVPFADLSNMEIGMKIALEGLRVTIP----PGISPHMCKLMKICMN 232

                         90
                 ....*....|..
gi 767953763 101 gwaQNPDERPSF 112
Cdd:cd14057  233 ---EDPGKRPKF 241