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 1769156157 301 QWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGL 380
Cdd:cd08786     1 QWIASKREEIVSQMTEACLNQSLDALLSRQLLMREDYELISTKPTRTSKVRQLLDTCDCQGEEFARVVVQKLKDNKQMGL 80

                  ....*..
gi 1769156157 381 QPYPEIL 387
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 1769156157 301 QWIQSKREDIVNQMTEACLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKDNKQMGL 380
Cdd:cd08786     1 QWIASKREEIVSQMTEACLNQSLDALLSRQLLMREDYELISTKPTRTSKVRQLLDTCDCQGEEFARVVVQKLKDNKQMGL 80

                  ....*..
gi 1769156157 381 QPYPEIL 387
Cdd:cd08786    81 QPYPDII 87

Protein tyrosine and serine/threonine kinase; Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyze the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyze the reverse process. Protein kinases fall into three broad classes, characterized with respect to substrate specificity; Serine/threonine-protein kinases, tyrosine-protein kinases, and dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins). This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include the catalytic domain of dual specificity kinases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157   4 PLLHHDLKTQNILLDNEFHVKIADFGLSKwrmmslSQSRSSKSAPEGGTII---YMPPE--NYepgqkSRASIKHDIYSY 78
Cdd:pfam07714 122 NFVHRDLAARNCLVSENLVVKISDFGLSR------DIYDDDYYRKRGGGKLpikWMAPEslKD-----GKFTSKSDVWSF 190

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1769156157  79 AVITWEVLSR-KQPFEDVTNPlQIMYSVSQGHRPVIneeslPYDIPhrARMISLIESGWAQNPDERPSFLKCLIEL 153
Cdd:pfam07714 191 GVLLWEIFTLgEQPYPGMSNE-EVLEFLEDGYRLPQ-----PENCP--DELYDLMKQCWAYDPEDRPTFSELVEDL 258

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157   5 LLHHDLKTQNILLDNEFHVKIADFGLSKwrmmslsQSRSSKSAPEG---GTIIYMPPENYEPGQKSRASikhDIYSYAVI 81
Cdd:COG0515   128 IVHRDIKPANILLTPDGRVKLIDFGIAR-------ALGGATLTQTGtvvGTPGYMAPEQARGEPVDPRS---DVYSLGVT 197

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1769156157  82 TWEVLSRKQPFeDVTNPLQIMYSVSqgHRPVINEESLPYDIPHR-----ARMIsliesgwAQNPDERPS 145
Cdd:COG0515   198 LYELLTGRPPF-DGDSPAELLRAHL--REPPPPPSELRPDLPPAldaivLRAL-------AKDPEERYQ 256

Stk1 family PASTA domain-containing Ser/Thr kinase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157   7 HHDLKTQNILLDNEFHVKIADFGLSkwR------------MMslsqsrssksapegGTIIYMPPEnyepgQ--KSRASIK 72
Cdd:NF033483  130 HRDIKPQNILITKDGRVKVTDFGIA--RalssttmtqtnsVL--------------GTVHYLSPE-----QarGGTVDAR 188

                          90       100
                  ....*....|....*....|.
gi 1769156157  73 HDIYSYAVITWEVLSRKQPFE 93
Cdd:NF033483  189 SDIYSLGIVLYEMLTGRPPFD 209

Catalytic domain of the Serine/Threonine kinase, Receptor Interacting Protein; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RIP kinases serve as essential sensors of cellular stress. They are involved in regulating NF-kappaB and MAPK signaling, and are implicated in mediating cellular processes such as apoptosis, necroptosis, differentiation, and survival. RIP kinases contain a homologous N-terminal kinase domain and varying C-terminal domains. Higher vertebrates contain multiple RIP kinases, with mammals harboring at least five members. RIP1 and RIP2 harbor C-terminal domains from the Death domain (DD) superfamily while RIP4 contains ankyrin (ANK) repeats. RIP3 contain a RIP homotypic interaction motif (RHIM) that facilitates binding to RIP1. RIP1 and RIP3 are important in apoptosis and necroptosis, while RIP2 and RIP4 play roles in keratinocyte differentiation and inflammatory immune responses. The RIP 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 1769156157   1 MTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPENYEPGQKsRASIKHDIYSYAV 80
Cdd:cd13978   112 MDPPLLHHDLKPENILLDNHFHVKISDFGLSKLGMKSISANRRRGTENLGGTPIYMAPEAFDDFNK-KPTSKSDVYSFAI 190

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1769156157  81 ITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIESGWAQNPDERPSFLKCLIEL 153
Cdd:cd13978   191 VIWAVLTRKEPFENAINPLLIMQIVSKGDRPSLDDIGRLKQIENVQELISLMIRCWDGNPDARPTFLECLDRL 263

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 1769156157   1 MTPPLLHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSApeGGTIIYMPPENYEpgQKSRAS-IKHDIYSYA 79
Cdd:cd14025   111 MKPPLLHLDLKPANILLDAHYHVKISDFGLAKWNGLSHSHDLSRDGL--RGTIAYLPPERFK--EKNRCPdTKHDVYSFA 186

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1769156157  80 VITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPVIneESLPYDIPHRA-RMISLIESGWAQNPDERPSFLKCLIELEPVL 157
Cdd:cd14025   187 IVIWGILTQKKPFAGENNILHIMVKVVKGHRPSL--SPIPRQRPSECqQMICLMKRCWDQDPRKRPTFQDITSETENLL 263

Catalytic domain of the Serine/Threonine kinase, Receptor Interacting Protein 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RIP1 harbors a C-terminal Death domain (DD), which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 can also recruit other kinases including MEKK1, MEKK3, and RIP3 through an intermediate domain (ID) that bears a RIP homotypic interaction motif (RHIM). RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accummulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. RIP kinases serve as essential sensors of cellular stress. The RIP1 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 1769156157   5 LLHHDLKTQNILLDNEFHVKIADFGLSKWRMMS--------LSQSRSSKSAPEGGTIIYMPPE-----NYEPGQKSrasi 71
Cdd:cd14027   111 VIHKDLKPENILVDNDFHIKIADLGLASFKMWSkltkeehnEQREVDGTAKKNAGTLYYMAPEhlndvNAKPTEKS---- 186

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1769156157  72 khDIYSYAVITWEVLSRKQPFEDVTNPLQIMYSVSQGHRPviNEESLPYDIPHRArmISLIESGWAQNPDERPSFLKC 149
Cdd:cd14027   187 --DVYSFAIVLWAIFANKEPYENAINEDQIIMCIKSGNRP--DVDDITEYCPREI--IDLMKLCWEANPEARPTFPGI 258

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157    4 PLLHHDLKTQNILLDNEFHVKIADFGLSKwrmmslSQSRSSKSAPEGGTIIY--MPPENYepgQKSRASIKHDIYSYAVI 81
Cdd:smart00219 122 NFIHRDLAARNCLVGENLVVKISDFGLSR------DLYDDDYYRKRGGKLPIrwMAPESL---KEGKFTSKSDVWSFGVL 192

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1769156157   82 TWEVLSR-KQPFEDVTNpLQIMYSVSQGHRPvineeslpyDIPHR--ARMISLIESGWAQNPDERPSFLKCLIEL 153
Cdd:smart00219 193 LWEIFTLgEQPYPGMSN-EEVLEYLKNGYRL---------PQPPNcpPELYDLMLQCWAEDPEDRPTFSELVEIL 257

Catalytic domain of Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. They can be classified into receptor and non-receptor tyr kinases. PTKs play important roles in many cellular processes including, lymphocyte activation, epithelium growth and maintenance, metabolism control, organogenesis regulation, survival, proliferation, differentiation, migration, adhesion, motility, and morphogenesis. Receptor tyr kinases (RTKs) are integral membrane proteins which contain an extracellular ligand-binding region, a transmembrane segment, and an intracellular tyr kinase domain. RTKs are usually activated through ligand binding, which causes dimerization and autophosphorylation of the intracellular tyr kinase catalytic domain, leading to intracellular signaling. Some RTKs are orphan receptors with no known ligands. Non-receptor (or cytoplasmic) tyr kinases are distributed in different intracellular compartments and are usually multi-domain proteins containing a catalytic tyr kinase domain as well as various regulatory domains such as SH3 and SH2. PTKs are usually autoinhibited and require a mechanism for activation. In many PTKs, the phosphorylation of tyr residues in the activation loop is essential for optimal activity. Aberrant expression of PTKs is associated with many development abnormalities and cancers.The PTK family is part of a larger superfamily that includes the catalytic domains of serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157   4 PLLHHDLKTQNILLDNEFHVKIADFGLSKWrmmslSQSRSSKSAPEGGTII--YMPPENYEPGQKSRASikhDIYSYAVI 81
Cdd:cd00192   125 KFVHRDLAARNCLVGEDLVVKISDFGLSRD-----IYDDDYYRKKTGGKLPirWMAPESLKDGIFTSKS---DVWSFGVL 196

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1769156157  82 TWEVLSR-KQPFEDVTNpLQIMYSVSQGHRPvineeSLPYDIPHraRMISLIESGWAQNPDERPSFLKCLIELE 154
Cdd:cd00192   197 LWEIFTLgATPYPGLSN-EEVLEYLRKGYRL-----PKPENCPD--ELYELMLSCWQLDPEDRPTFSELVERLE 262

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 1769156157   1 MTPPLLHHDLKTQNILLDNEFHVKIADFGLSkwRMMSLSQSRSSKSAPegGTIIYMPPENYEpgQKSRASIKHDIYSYAV 80
Cdd:cd14064   112 LTQPIIHRDLNSHNILLYEDGHAVVADFGES--RFLQSLDEDNMTKQP--GNLRWMAPEVFT--QCTRYSIKADVFSYAL 185

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1769156157  81 ITWEVLSRKQPFEDVtNPLQIMYSVSQGH-RPVIneeslPYDIPhrARMISLIESGWAQNPDERPSFLKCLIELEP 155
Cdd:cd14064   186 CLWELLTGEIPFAHL-KPAAAAADMAYHHiRPPI-----GYSIP--KPISSLLMRGWNAEPESRPSFVEIVALLEP 253

Catalytic domain of the Serine/Threonine Kinases, Mixed Lineage Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which 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. Mammals have four MLKs (MLK1-4), 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 MLK 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 1769156157   4 PLLHHDLKTQNILLDN-------EFHV-KIADFGLSK-W----RMmslsqsrssksaPEGGTIIYMPPENYEPGQKSRAS 70
Cdd:cd14061   115 PIIHRDLKSSNILILEaienedlENKTlKITDFGLAReWhkttRM------------SAAGTYAWMAPEVIKSSTFSKAS 182

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157  71 ikhDIYSYAVITWEVLSRKQPFEDVtNPLQIMYSVSqghrpvINEESLPydIPHR--ARMISLIESGWAQNPDERPSFLK 148
Cdd:cd14061   183 ---DVWSYGVLLWELLTGEVPYKGI-DGLAVAYGVA------VNKLTLP--IPSTcpEPFAQLMKDCWQPDPHDRPSFAD 250

                  ....*.
gi 1769156157 149 CLIELE 154
Cdd:cd14061   251 ILKQLE 256

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 1769156157   5 LLHHDLKTQNILLDNEFHVKIADFGLSKWRmmslSQSRSSKSAPEGGTIIYMPPENYEPGQKSRASikhDIYSYAVITWE 84
Cdd:cd14014   121 IVHRDIKPANILLTEDGRVKLTDFGIARAL----GDSGLTQTGSVLGTPAYMAPEQARGGPVDPRS---DIYSLGVVLYE 193

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1769156157  85 VLSRKQPFEDVTnPLQIMYsvSQGHRPVINEESLPYDIPhrARMISLIESGWAQNPDERPS 145
Cdd:cd14014   194 LLTGRPPFDGDS-PAAVLA--KHLQEAPPPPSPLNPDVP--PALDAIILRALAKDPEERPQ 249

Catalytic domain of the Serine/Threonine kinases, Interleukin-1 Receptor Associated Kinases and related STKs; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. Some IRAKs may also play roles in T- and B-cell signaling, and adaptive immunity. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK-1, -2, and -4 are ubiquitously expressed and are active kinases, while IRAK-M is only induced in monocytes and macrophages and is an inactive kinase. Variations in IRAK genes are linked to diverse diseases including infection, sepsis, cancer, and autoimmune diseases. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain (a pseudokinase domain in the case of IRAK3), and a C-terminal domain; IRAK-4 lacks the C-terminal domain. This subfamily includes plant receptor-like kinases (RLKs) including Arabidopsis thaliana BAK1 and CLAVATA1 (CLV1). BAK1 functions in BR (brassinosteroid)-regulated plant development and in pathways involved in plant resistance to pathogen infection and herbivore attack. CLV1, directly binds small signaling peptides, CLAVATA3 (CLV3) and CLAVATA3/EMBRYO SURROUNDING REGI0N (CLE), to restrict stem cell proliferation: the CLV3-CLV1-WUS (WUSCHEL) module influences stem cell maintenance in the shoot apical meristem, and the CLE40 (CLAVATA3/EMBRYO SURROUNDING REGION40) -ACR4 (CRINKLY4) -CLV1- WOX5 (WUSCHEL-RELATED HOMEOBOX5) module at the root apical meristem. The IRAK 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 1769156157   3 PPLLHHDLKTQNILLDNEFHVKIADFGLSkwRMMSLSQSRSSKSAPEgGTIIYMPPENYEPGqksRASIKHDIYSYAVIT 82
Cdd:cd14066   115 PPIIHGDIKSSNILLDEDFEPKLTDFGLA--RLIPPSESVSKTSAVK-GTIGYLAPEYIRTG---RVSTKSDVYSFGVVL 188

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157  83 WEVLSRKQPFEDVTNPLQIMYSVS--QGHRPVINEE----SLPYDIPHR----ARMISLIESGWAQNPDERPSFLKCLIE 152
Cdd:cd14066   189 LELLTGKPAVDENRENASRKDLVEwvESKGKEELEDildkRLVDDDGVEeeevEALLRLALLCTRSDPSLRPSMKEVVQM 268

                  ...
gi 1769156157 153 LEP 155
Cdd:cd14066   269 LEK 271

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 1769156157 300 QQWIQSKREDIVNQMTeaCLNQSLDALLSRDLIMKEDYELVSTKPTRTSKVRQLLDTTDIQGEEFAKVIVQKLKdNKQMG 379
Cdd:pfam00619   1 RKLLKKNRVALVERLG--TLDGLLDYLLEKNVLTEEEEEKIKANPTRLDKARELLDLVLKKGPKACQIFLEALK-EGDPD 77

                  ....*...
gi 1769156157 380 LQPYPEIL 387
Cdd:pfam00619  78 LASDLEGL 85

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 1769156157   6 LHHDLKTQNILLDNEFHVKIADFGLskWRMMSLSQSRSSKSAPEGGTIIYMPPE---NYEPGQksRASIKHDIYSYAVIT 82
Cdd:cd13992   120 YHGRLKSSNCLVDSRWVVKLTDFGL--RNLLEEQTNHQLDEDAQHKKLLWTAPEllrGSLLEV--RGTQKGDVYSFAIIL 195

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1769156157  83 WEVLSRKQPFEDVTnPLQIMYSVSQGHRPVINEESLPYDIPHRARMISLIESGWAQNPDERPSF 146
Cdd:cd13992   196 YEILFRSDPFALER-EVAIVEKVISGGNKPFRPELAVLLDEFPPRLVLLVKQCWAENPEKRPSF 258

Catalytic domain of the Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The Nek family is composed of 11 different mammalian members (Nek1-11) with similarity to the catalytic domain of Aspergillus nidulans NIMA kinase, the founding member of the Nek family, which was identified in a screen for cell cycle mutants that were prevented from entering mitosis. Neks contain a conserved N-terminal catalytic domain and a more divergent C-terminal regulatory region of various sizes and structures. They are involved in the regulation of downstream processes following the activation of Cdc2, and many of their functions are cell cycle-related. They play critical roles in microtubule dynamics during ciliogenesis and mitosis. The Nek family 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 1769156157   6 LHHDLKTQNILLDNEFHVKIADFGLSKwrMMSLSQSRSSKSApegGTIIYMPPE---NYEPGQKSrasikhDIYSYAVIT 82
Cdd:cd08215   125 LHRDLKTQNIFLTKDGVVKLGDFGISK--VLESTTDLAKTVV---GTPYYLSPElceNKPYNYKS------DIWALGCVL 193

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1769156157  83 WEVLSRKQPFEDvTNPLQIMYSVSQGHRPVINEeslPYDiphrARMISLIESGWAQNPDERPS 145
Cdd:cd08215   194 YELCTLKHPFEA-NNLPALVYKIVKGQYPPIPS---QYS----SELRDLVNSMLQKDPEKRPS 248

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 1769156157   6 LHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPeggtIIYMPPENYEpgqKSRASIKHDIYSYAVITWEV 85
Cdd:cd05059   122 IHRDLAARNCLVGEQNVVKVSDFGLARYVLDDEYTSSVGTKFP----VKWSPPEVFM---YSKFSSKSDVWSFGVLMWEV 194

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1769156157  86 LSR-KQPFEDVTNpLQIMYSVSQGHRpvineeslpYDIPHRARM--ISLIESGWAQNPDERPSFLKCL 150
Cdd:cd05059   195 FSEgKMPYERFSN-SEVVEHISQGYR---------LYRPHLAPTevYTIMYSCWHEKPEERPTFKILL 252

Catalytic domain of the Protein Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase 9; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Nek9, also called Nercc1, is primarily a cytoplasmic protein but can also localize in the nucleus. It is involved in modulating chromosome alignment and splitting during mitosis. It interacts with the gamma-tubulin ring complex and the Ran GTPase, and is implicated in microtubule organization. Nek9 associates with FACT (FAcilitates Chromatin Transcription) and modulates interphase progression. It also interacts with Nek6, and Nek7, during mitosis, resulting in their activation. Nek9 is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control. The Nek family 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 1769156157   5 LLHHDLKTQNILLDNEFHVKIADFGLSK-----WRMMSLSQsrssksapegGTIIYMPPENYepgQKSRASIKHDIYSYA 79
Cdd:cd08221   122 ILHRDIKTLNIFLTKADLVKLGDFGISKvldseSSMAESIV----------GTPYYMSPELV---QGVKYNFKSDIWAVG 188

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1769156157  80 VITWEVLSRKQPFeDVTNPLQIMYSVSQGHRPVINEEslpydipHRARMISLIESGWAQNPDERPS 145
Cdd:cd08221   189 CVLYELLTLKRTF-DATNPLRLAVKIVQGEYEDIDEQ-------YSEEIIQLVHDCLHQDPEDRPT 246

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 1769156157   6 LHHDLKTQNILLDNEFHVKIADFGLSKWRMMSLSQSRSSKSAPeggtIIYMPPENYepgQKSRASIKHDIYSYAVITWEV 85
Cdd:cd05113   122 LHRDLAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFP----VRWSPPEVL---MYSKFSSKSDVWAFGVLMWEV 194

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1769156157  86 LSR-KQPFEDVTNPlQIMYSVSQGHRPVineeslpydIPHRA--RMISLIESGWAQNPDERPSFLKCLIELE 154
Cdd:cd05113   195 YSLgKMPYERFTNS-ETVEHVSQGLRLY---------RPHLAseKVYTIMYSCWHEKADERPTFKILLSNIL 256

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 1769156157   5 LLHHDLKTQNILLDNEfHVKIADFGLSKWRMMSLSQSRSSKSAPEGGTIIYMPPE---NYEPGQKSRASI----KHDIYS 77
Cdd:cd14063   118 IIHKDLKSKNIFLENG-RVVITDFGLFSLSGLLQPGRREDTLVIPNGWLCYLAPEiirALSPDLDFEESLpftkASDVYA 196

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1769156157  78 YAVITWEVLSRKQPFEDvTNPLQIMYSVSQGHRPVINEESLPYDIPhrarmiSLIESGWAQNPDERPSF 146
Cdd:cd14063   197 FGTVWYELLAGRWPFKE-QPAESIIWQVGCGKKQSLSQLDIGREVK------DILMQCWAYDPEKRPTF 258

Catalytic domain of Spleen Tyrosine Kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The Syk-like subfamily is composed of Syk, ZAP-70, Shark, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing two Src homology 2 (SH2) domains N-terminal to the catalytic tyr kinase domain. They are involved in the signaling downstream of activated receptors (including B-cell, T-cell, and Fc receptors) that contain ITAMs (immunoreceptor tyr activation motifs), leading to processes such as cell proliferation, differentiation, survival, adhesion, migration, and phagocytosis. Syk is important in B-cell receptor signaling, while Zap-70 is primarily expressed in T-cells and NK cells, and is a crucial component in T-cell receptor signaling. Syk also plays a central role in Fc receptor-mediated phagocytosis in the adaptive immune system. Shark is exclusively expressed in ectodermally derived epithelia, and is localized preferentially to the apical surface of the epithelial cells, it may play a role in a signaling pathway for epithelial cell polarity. The Syk-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 1769156157   7 HHDLKTQNILLDNEFHVKIADFGLSKwrmmSLSQSRSSKSAPEGGT--IIYMPPE--NYepgqkSRASIKHDIYSYAVIT 82
Cdd:cd05060   118 HRDLAARNVLLVNRHQAKISDFGMSR----ALGAGSDYYRATTAGRwpLKWYAPEciNY-----GKFSSKSDVWSYGVTL 188

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1769156157  83 WEVLSR-KQPFEDVTNPlQIMYSVSQGHRpvineESLPYDIPhrARMISLIESGWAQNPDERPSFLkcliELEPVLRT 159
Cdd:cd05060   189 WEAFSYgAKPYGEMKGP-EVIAMLESGER-----LPRPEECP--QEIYSIMLSCWKYRPEDRPTFS----ELESTFRR 254

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 1769156157   5 LLHHDLKTQNILLDNEFHVKIADFGL----SKWRMMSLSQSRSsksapegGTIIYMPPENYEPGQKSRASIKHDIYSYAV 80
Cdd:cd14151   125 IIHRDLKSNNIFLHEDLTVKIGDFGLatvkSRWSGSHQFEQLS-------GSILWMAPEVIRMQDKNPYSFQSDVYAFGI 197

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1769156157  81 ITWEVLSRKQPFEDVTNPLQIMYSVSQGH-RPVINEesLPYDIPhrARMISLIESGWAQNPDERPSFLKCLIELEPVLRT 159
Cdd:cd14151   198 VLYELMTGQLPYSNINNRDQIIFMVGRGYlSPDLSK--VRSNCP--KAMKRLMAECLKKKRDERPLFPQILASIELLARS 273

                  .
gi 1769156157 160 F 160
Cdd:cd14151   274 L 274