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 767973837 208 QVIREGGHAVVWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGRLLSGPLLVLELHPKdc 287
Cdd:cd14054    1 QLIGQGRYGTVWKGSLDERPVAVKVFPARHRQNFQNEKDIYELPLMEHSNILRFIGADERPTADGRMEYLLVLEYAPK-- 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 288 vclcprgraphnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEERWQNGQYKPGIAHRDLSSQNVLIREDGSC 367
Cdd:cd14054   79 -----------------GSLCSYLRENTLDWMSSCRMALSLTRGLAYLHTDLRRGDQYKPAIAHRDLNSRNVLVKADGSC 141

                        170       180       190
                 ....*....|....*....|....*....|...
gi 767973837 368 AIGDLGLALVLPGLTQPpaWTPTQPQGPAAIME 400
Cdd:cd14054  142 VICDFGLAMVLRGSSLV--RGRPGAAENASISE 172

Catalytic domain of the Serine/Threonine Kinases, Bone Morphogenetic Protein and Anti-Muellerian Hormone Type II Receptors; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BMPR2 and AMHR2 belong to a group of receptors for the TGFbeta family of secreted signaling molecules that includes TGFbeta, BMPs, activins, growth and differentiation factors (GDFs), and AMH, among others. These receptors contain an extracellular domain that binds ligands, a single transmembrane region, and a cytoplasmic catalytic kinase domain. Type II receptors are high-affinity receptors which bind ligands, autophosphorylate, as well as trans-phosphorylate and activate low-affinity type I receptors. BMPR2 and AMHR2 act primarily as a receptor for BMPs and AMH, respectively. BMPs induce bone and cartilage formation, as well as regulate tooth, kidney, skin, hair, haematopoietic, and neuronal development. Mutations in BMPR2A is associated with familial pulmonary arterial hypertension. AMH is mainly responsible for the regression of Mullerian ducts during male sex differentiation. It is expressed exclusively by somatic cells of the gonads. Mutations in either AMH or AMHR2 cause persistent Mullerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism characterized by the presence of Mullerian derivatives (ovary and tubes) in otherwise normally masculine males. The BMPR2/AMHR2 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 767973837 208 QVIREGGHAVVWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGRLLSGPLLVLELHPKdc 287
Cdd:cd14054    1 QLIGQGRYGTVWKGSLDERPVAVKVFPARHRQNFQNEKDIYELPLMEHSNILRFIGADERPTADGRMEYLLVLEYAPK-- 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 288 vclcprgraphnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEERWQNGQYKPGIAHRDLSSQNVLIREDGSC 367
Cdd:cd14054   79 -----------------GSLCSYLRENTLDWMSSCRMALSLTRGLAYLHTDLRRGDQYKPAIAHRDLNSRNVLVKADGSC 141

                        170       180       190
                 ....*....|....*....|....*....|...
gi 767973837 368 AIGDLGLALVLPGLTQPpaWTPTQPQGPAAIME 400
Cdd:cd14054  142 VICDFGLAMVLRGSSLV--RGRPGAAENASISE 172

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 208 QVIREGGHAVVWAG--QLQGKLVAIK------AFPPRSVAQFQAERALyeLPGLQHDHIVRFITASRGGPGrllsgPLLV 279
Cdd:COG0515   13 RLLGRGGMGVVYLArdLRLGRPVALKvlrpelAADPEARERFRREARA--LARLNHPNIVRVYDVGEEDGR-----PYLV 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 280 LELHPkdcvclcprGRaphnslcpigSLCHYLTQYTS-DWGSSLRMALSLAQGLAFLHEErwqngqykpGIAHRDLSSQN 358
Cdd:COG0515   86 MEYVE---------GE----------SLADLLRRRGPlPPAEALRILAQLAEALAAAHAA---------GIVHRDIKPAN 137

                        170       180
                 ....*....|....*....|....*...
gi 767973837 359 VLIREDGSCAIGDLGLALVLPG--LTQP 384
Cdd:COG0515  138 ILLTPDGRVKLIDFGIARALGGatLTQT 165

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 767973837  208 QVIREGGHAVVWAGQLQGK------LVAIKAFPP----RSVAQFQAERALyeLPGLQHDHIVRFITA-SRGGPgrllsgP 276
Cdd:pfam07714   5 EKLGEGAFGEVYKGTLKGEgentkiKVAVKTLKEgadeEEREDFLEEASI--MKKLDHPNIVKLLGVcTQGEP------L 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837  277 LLVLELhpkdcvclcprgraphnslCPIGSLCHYLTQYTSDWGSS--LRMALSLAQGLAFLHEERwqngqykpgIAHRDL 354
Cdd:pfam07714  77 YIVTEY-------------------MPGGDLLDFLRKHKRKLTLKdlLSMALQIAKGMEYLESKN---------FVHRDL 128

                         170       180
                  ....*....|....*....|.
gi 767973837  355 SSQNVLIREDGSCAIGDLGLA 375
Cdd:pfam07714 129 AARNCLVSENLVVKISDFGLS 149

Catalytic domain of the Serine/Threonine Kinases, Bone Morphogenetic Protein and Anti-Muellerian Hormone Type II Receptors; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BMPR2 and AMHR2 belong to a group of receptors for the TGFbeta family of secreted signaling molecules that includes TGFbeta, BMPs, activins, growth and differentiation factors (GDFs), and AMH, among others. These receptors contain an extracellular domain that binds ligands, a single transmembrane region, and a cytoplasmic catalytic kinase domain. Type II receptors are high-affinity receptors which bind ligands, autophosphorylate, as well as trans-phosphorylate and activate low-affinity type I receptors. BMPR2 and AMHR2 act primarily as a receptor for BMPs and AMH, respectively. BMPs induce bone and cartilage formation, as well as regulate tooth, kidney, skin, hair, haematopoietic, and neuronal development. Mutations in BMPR2A is associated with familial pulmonary arterial hypertension. AMH is mainly responsible for the regression of Mullerian ducts during male sex differentiation. It is expressed exclusively by somatic cells of the gonads. Mutations in either AMH or AMHR2 cause persistent Mullerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism characterized by the presence of Mullerian derivatives (ovary and tubes) in otherwise normally masculine males. The BMPR2/AMHR2 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 767973837 208 QVIREGGHAVVWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGRLLSGPLLVLELHPKdc 287
Cdd:cd14054    1 QLIGQGRYGTVWKGSLDERPVAVKVFPARHRQNFQNEKDIYELPLMEHSNILRFIGADERPTADGRMEYLLVLEYAPK-- 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 288 vclcprgraphnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEERWQNGQYKPGIAHRDLSSQNVLIREDGSC 367
Cdd:cd14054   79 -----------------GSLCSYLRENTLDWMSSCRMALSLTRGLAYLHTDLRRGDQYKPAIAHRDLNSRNVLVKADGSC 141

                        170       180       190
                 ....*....|....*....|....*....|...
gi 767973837 368 AIGDLGLALVLPGLTQPpaWTPTQPQGPAAIME 400
Cdd:cd14054  142 VICDFGLAMVLRGSSLV--RGRPGAAENASISE 172

Catalytic domain of the Serine/Threonine Kinase, Activin Type II Receptor; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. ACVR2 belongs to a group of receptors for the TGFbeta family of secreted signaling molecules that includes TGFbeta, bone morphogenetic proteins (BMPs), activins, growth and differentiation factors (GDFs), and anti-Mullerian hormone, among others. These receptors contain an extracellular domain that binds ligands, a single transmembrane region, and a cytoplasmic catalytic kinase domain. Type II receptors, such as ACVR2, are high-affinity receptors which bind ligands, autophosphorylate, as well as trans-phosphorylate and activate low-affinity type I receptors. ACVR2 acts primarily as the receptors for activins, nodal, myostatin, GDF11, and a subset of BMPs. ACVR2 signaling impacts many cellular and physiological processes including reproductive and gonadal functions, myogenesis, bone remodeling and tooth development, kidney organogenesis, apoptosis, fibrosis, inflammation, and neurogenesis. Vertebrates contain two ACVR2 proteins, ACVR2a (or ActRIIA) and ACVR2b (or ActRIIB). The ACVR2 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 767973837 218 VWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGrLLSGPLLVLELHPKdcvclcprgrap 297
Cdd:cd14053   11 VWKAQYLNRLVAVKIFPLQEKQSWLTEREIYSLPGMKHENILQFIGAEKHGES-LEAEYWLITEFHER------------ 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 298 hnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEER-WQNGQYKPGIAHRDLSSQNVLIREDGSCAIGDLGLAL 376
Cdd:cd14053   78 -------GSLCDYLKGNVISWNELCKIAESMARGLAYLHEDIpATNGGHKPSIAHRDFKSKNVLLKSDLTACIADFGLAL 150

                 ..
gi 767973837 377 VL 378
Cdd:cd14053  151 KF 152

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 767973837 218 VWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPG---RLLsgplLVLELHPKdcvclcprg 294
Cdd:cd14056   11 VWLGKYRGEKVAVKIFSSRDEDSWFRETEIYQTVMLRHENILGFIAADIKSTGswtQLW----LITEYHEH--------- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 295 raphnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEERWQNgQYKPGIAHRDLSSQNVLIREDGSCAIGDLGL 374
Cdd:cd14056   78 ----------GSLYDYLQRNTLDTEEALRLAYSAASGLAHLHTEIVGT-QGKPAIAHRDLKSKNILVKRDGTCCIADLGL 146

                 ...
gi 767973837 375 ALV 377
Cdd:cd14056  147 AVR 149

Catalytic domain of the Serine/Threonine Kinases, Transforming Growth Factor beta Type I Receptor and Activin Type IB/IC Receptors; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TGFbR1, also called Activin receptor-Like Kinase 5 (ALK5), functions as a receptor for TGFbeta and phoshorylates SMAD2/3. TGFbeta proteins are cytokines that regulate cell growth, differentiation, and survival, and are critical in the development and progression of many human cancers. Mutations in TGFbR1 (and TGFbR2) can cause aortic aneurysm disorders such as Loeys-Dietz and Marfan syndromes. ACVR1b (also called ALK4) and ACVR1c (also called ALK7) act as receptors for activin A and B, respectively. TGFbR1, ACVR1b, and ACVR1c belong to a group of receptors for the TGFbeta family of secreted signaling molecules that includes 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, like TGFbR1, ACVR1b, and ACVR1c, are low-affinity receptors that bind ligands only after they are recruited by the ligand/type II high-affinity receptor complex. Following activation, 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. The TGFbR1 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 767973837 208 QVIREGGHAVVWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGrLLSGPLLVLELHPKdc 287
Cdd:cd14143    1 ESIGKGRFGEVWRGRWRGEDVAVKIFSSREERSWFREAEIYQTVMLRHENILGFIAADNKDNG-TWTQLWLVSDYHEH-- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 288 vclcprgraphnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEErWQNGQYKPGIAHRDLSSQNVLIREDGSC 367
Cdd:cd14143   78 -----------------GSLFDYLNRYTVTVEGMIKLALSIASGLAHLHME-IVGTQGKPAIAHRDLKSKNILVKKNGTC 139

                 ....*....
gi 767973837 368 AIGDLGLAL 376
Cdd:cd14143  140 CIADLGLAV 148

Catalytic domain of the Serine/Threonine Kinase, Bone Morphogenetic Protein Type I Receptor; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BMPR1 functions as a receptor for morphogenetic proteins (BMPs), which are involved in the regulation of cell proliferation, survival, differentiation, and apoptosis. BMPs are able to induce bone, cartilage, ligament, and tendon formation, and may play roles in bone diseases and tumors. Vertebrates contain two type I BMP receptors, BMPR1a and BMPR1b. BMPR1 belongs to a group of receptors for the TGFbeta family of secreted signaling molecules that also includes TGFbeta, 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, like BMPR1, are low-affinity receptors that bind ligands only after they are recruited by the ligand/type II high-affinity receptor complex. Following activation, 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. The BMPR1 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 767973837 208 QVIREGGHAVVWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGRLlSGPLLVLELHPkdc 287
Cdd:cd14144    1 RSVGKGRYGEVWKGKWRGEKVAVKIFFTTEEASWFRETEIYQTVLMRHENILGFIAADIKGTGSW-TQLYLITDYHE--- 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 288 vclcprgraphnslcpIGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEERWQNgQYKPGIAHRDLSSQNVLIREDGSC 367
Cdd:cd14144   77 ----------------NGSLYDFLRGNTLDTQSMLKLAYSAACGLAHLHTEIFGT-QGKPAIAHRDIKSKNILVKKNGTC 139

                 ....*...
gi 767973837 368 AIGDLGLA 375
Cdd:cd14144  140 CIADLGLA 147

Catalytic domain of the Serine/Threonine Kinase, Bone Morphogenetic Protein Type IA Receptor; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BMPR1a, also called Activin receptor-Like Kinase 3 (ALK3), functions as a receptor for bone morphogenetic proteins (BMPs), which are involved in the regulation of cell proliferation, survival, differentiation, and apoptosis. BMPs are able to induce bone, cartilage, ligament, and tendon formation, and may play roles in bone diseases and tumors. Germline mutations in BMPR1a are associated with an increased risk to Juvenile Polyposis Syndrome, a hamartomatous disorder that may lead to gastrointestinal cancer. BMPR1a may also play an indirect role in the development of hematopoietic stem cells (HSCs) as osteoblasts are a major component of the HSC niche within the bone marrow. BMPR1a belongs to a group of receptors for the TGFbeta family of secreted signaling molecules that includes TGFbeta, BMPs, 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, like BMPR1a, are low-affinity receptors that bind ligands only after they are recruited by the ligand/type II high-affinity receptor complex. Following activation, 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. The BMPR1a 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 767973837 210 IREGGHAVVWAGQLQGKLVAIKAFPPRSVAQFQAERALYELPGLQHDHIVRFITASRGGPGRLlSGPLLVLELHPKdcvc 289
Cdd:cd14220    3 IGKGRYGEVWMGKWRGEKVAVKVFFTTEEASWFRETEIYQTVLMRHENILGFIAADIKGTGSW-TQLYLITDYHEN---- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 290 lcprgraphnslcpiGSLCHYLTQYTSDWGSSLRMALSLAQGLAFLHEERWQNgQYKPGIAHRDLSSQNVLIREDGSCAI 369
Cdd:cd14220   78 ---------------GSLYDFLKCTTLDTRALLKLAYSAACGLCHLHTEIYGT-QGKPAIAHRDLKSKNILIKKNGTCCI 141

                 ....*..
gi 767973837 370 GDLGLAL 376
Cdd:cd14220  142 ADLGLAV 148

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 210 IREGGHAVVWAGQLQGKLVAIKAFPPRS-----VAQFQAERALyeLPGLQHDHIVRFITASRGGPgrllsgPL-LVLELh 283
Cdd:cd13999    1 IGSGSFGEVYKGKWRGTDVAIKKLKVEDdndelLKEFRREVSI--LSKLRHPNIVQFIGACLSPP------PLcIVTEY- 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 284 pkdcvclcprgraphnslCPIGSLCHYLT--QYTSDWGSSLRMALSLAQGLAFLHEerwqngqykPGIAHRDLSSQNVLI 361
Cdd:cd13999   72 ------------------MPGGSLYDLLHkkKIPLSWSLRLKIALDIARGMNYLHS---------PPIIHRDLKSLNILL 124

                        170
                 ....*....|....
gi 767973837 362 REDGSCAIGDLGLA 375
Cdd:cd13999  125 DENFTVKIADFGLS 138

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 767973837 210 IREGGHAVVWAGQLQ--GKLVAIKAFPPRSVaQFQAERALYE---LPGLQHDHIVRFITASRGGPGRLLsgpllVLELhp 284
Cdd:cd00180    1 LGKGSFGKVYKARDKetGKKVAVKVIPKEKL-KKLLEELLREieiLKKLNHPNIVKLYDVFETENFLYL-----VMEY-- 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 285 kdcvclcprgraphnslCPIGSLCHYLTQYTS--DWGSSLRMALSLAQGLAFLHEErwqngqykpGIAHRDLSSQNVLIR 362
Cdd:cd00180   73 -----------------CEGGSLKDLLKENKGplSEEEALSILRQLLSALEYLHSN---------GIIHRDLKPENILLD 126

                        170
                 ....*....|...
gi 767973837 363 EDGSCAIGDLGLA 375
Cdd:cd00180  127 SDGTVKLADFGLA 139

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 767973837 210 IREGGHAVVWAGQLQ-GKLVAIKAFPPRSVA----QFQAEraLYELPGLQHDHIVRFITASRGGpgrllSGPLLVLELHP 284
Cdd:cd14066    1 IGSGGFGTVYKGVLEnGTVVAVKRLNEMNCAaskkEFLTE--LEMLGRLRHPNLVRLLGYCLES-----DEKLLVYEYMP 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 285 KdcvclcprgraphnslcpiGSLCHYLTQYTS----DWGSSLRMALSLAQGLAFLHEErwqngqYKPGIAHRDLSSQNVL 360
Cdd:cd14066   74 N-------------------GSLEDRLHCHKGspplPWPQRLKIAKGIARGLEYLHEE------CPPPIIHGDIKSSNIL 128

                        170
                 ....*....|....*....
gi 767973837 361 IREDGSCAIGDLGLALVLP 379
Cdd:cd14066  129 LDEDFEPKLTDFGLARLIP 147

Protein kinase; unclassified specificity; Phosphotransferases. The specificity of this class of kinases can not be predicted. Possible dual-specificity Ser/Thr/Tyr kinase.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837   208 QVIREGGHAVVWAGQLQGKL------VAIKAfpPRSVAQFQAERALYE----LPGLQHDHIVRFITASRGGPGrllsgPL 277
Cdd:smart00221   5 KKLGEGAFGEVYKGTLKGKGdgkeveVAVKT--LKEDASEQQIEEFLReariMRKLDHPNIVKLLGVCTEEEP-----LM 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837   278 LVLELhpkdcvclcprgraphnslCPIGSLCHYLTQYTSDWGSS---LRMALSLAQGLAFLHEERwqngqykpgIAHRDL 354
Cdd:smart00221  78 IVMEY-------------------MPGGDLLDYLRKNRPKELSLsdlLSFALQIARGMEYLESKN---------FIHRDL 129

                          170       180
                   ....*....|....*....|.
gi 767973837   355 SSQNVLIREDGSCAIGDLGLA 375
Cdd:smart00221 130 AARNCLVGENLVVKISDFGLS 150

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837   208 QVIREGGHAVVWAGQLQ--GKLVAIKAFPPRS----VAQFQAERALYELpgLQHDHIVRFITAsrggpgrllsgpllvle 281
Cdd:smart00220   5 EKLGEGSFGKVYLARDKktGKLVAIKVIKKKKikkdRERILREIKILKK--LKHPNIVRLYDV----------------- 65

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837   282 LHPKDCVCLCprgraphNSLCPIGSLCHYLTQY---TSDWgsSLRMALSLAQGLAFLHEErwqngqykpGIAHRDLSSQN 358
Cdd:smart00220  66 FEDEDKLYLV-------MEYCEGGDLFDLLKKRgrlSEDE--ARFYLRQILSALEYLHSK---------GIVHRDLKPEN 127

                          170
                   ....*....|....*..
gi 767973837   359 VLIREDGSCAIGDLGLA 375
Cdd:smart00220 128 ILLDEDGHVKLADFGLA 144

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 767973837  208 QVIREGGHAVVWAGQLQGK------LVAIKAFPP----RSVAQFQAERALyeLPGLQHDHIVRFITA-SRGGPgrllsgP 276
Cdd:pfam07714   5 EKLGEGAFGEVYKGTLKGEgentkiKVAVKTLKEgadeEEREDFLEEASI--MKKLDHPNIVKLLGVcTQGEP------L 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837  277 LLVLELhpkdcvclcprgraphnslCPIGSLCHYLTQYTSDWGSS--LRMALSLAQGLAFLHEERwqngqykpgIAHRDL 354
Cdd:pfam07714  77 YIVTEY-------------------MPGGDLLDFLRKHKRKLTLKdlLSMALQIAKGMEYLESKN---------FVHRDL 128

                         170       180
                  ....*....|....*....|.
gi 767973837  355 SSQNVLIREDGSCAIGDLGLA 375
Cdd:pfam07714 129 AARNCLVSENLVVKISDFGLS 149

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 767973837 217 VVWAGQLQGK-----LVAIKAfpPRSVAQFQAERALYE----LPGLQHDHIVRFI-TASRGGPgrllsgPLLVLELhpkd 286
Cdd:cd00192   10 EVYKGKLKGGdgktvDVAVKT--LKEDASESERKDFLKearvMKKLGHPNVVRLLgVCTEEEP------LYLVMEY---- 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 287 cvclcprgraphnslCPIGSLCHYLTQYTSDWGSS----------LRMALSLAQGLAFLHEERwqngqykpgIAHRDLSS 356
Cdd:cd00192   78 ---------------MEGGDLLDFLRKSRPVFPSPepstlslkdlLSFAIQIAKGMEYLASKK---------FVHRDLAA 133

                        170
                 ....*....|....*....
gi 767973837 357 QNVLIREDGSCAIGDLGLA 375
Cdd:cd00192  134 RNCLVGEDLVVKISDFGLS 152

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 213 GGHAVVWAG--QLQGKLVAIKAF-----PPRSVAQFQAERALyeLPGLQHDHIVRFITASRGGpgRLLSgplLVLELhpk 285
Cdd:cd06627   11 GAFGSVYKGlnLNTGEFVAIKQIslekiPKSDLKSVMGEIDL--LKKLNHPNIVKYIGSVKTK--DSLY---IILEY--- 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 286 dcvclcprgraphnslCPIGSLCHYLTQYtSDWGSSLrMALSLAQ---GLAFLHEErwqngqykpGIAHRDLSSQNVLIR 362
Cdd:cd06627   81 ----------------VENGSLASIIKKF-GKFPESL-VAVYIYQvleGLAYLHEQ---------GVIHRDIKGANILTT 133

                        170       180
                 ....*....|....*....|....
gi 767973837 363 EDGSCAIGDLGLALVLPGLTQPPA 386
Cdd:cd06627  134 KDGLVKLADFGVATKLNEVEKDEN 157

Catalytic domain of the Serine/Threonine Kinase, Cell Cycle-Related Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CCRK was previously called p42. It is a Cyclin-Dependent Kinase (CDK)-Activating Kinase (CAK) which is essential for the activation of CDK2. It is indispensable for cell growth and has been implicated in the progression of glioblastoma multiforme. In the heart, a splice variant of CCRK with a different C-terminal half is expressed; this variant promotes cardiac cell growth and survival and is significantly down-regulated during the development of heart failure. The CCRK 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 767973837 210 IREGGHAVVW-AGQLQ-GKLVAIKAFPPRSVAQFQAERALYELPGLQ----HDHIVRFITASRGGpgrllSGPLLVLELH 283
Cdd:cd07832    8 IGEGAHGIVFkAKDREtGETVALKKVALRKLEGGIPNQALREIKALQacqgHPYVVKLRDVFPHG-----TGFVLVFEYM 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767973837 284 PKDcvcLCPRGRAPHNSLcPIGSLCHYLtqytsdwgsslRMALslaQGLAFLHEERwqngqykpgIAHRDLSSQNVLIRE 363
Cdd:cd07832   83 LSS---LSEVLRDEERPL-TEAQVKRYM-----------RMLL---KGVAYMHANR---------IMHRDLKPANLLISS 135

                        170
                 ....*....|....
gi 767973837 364 DGSCAIGDLGLALV 377
Cdd:cd07832  136 TGVLKIADFGLARL 149

Catalytic domain of the Protein Tyrosine Kinase, Csk homologous kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Chk is also referred to as megakaryocyte-associated tyrosine kinase (Matk). Chk inhibits Src kinases using a noncatalytic mechanism by simply binding to them. As a negative regulator of Src kinases, Chk may play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. Chk is expressed in brain and hematopoietic cells. Like Csk, it is a cytoplasmic (or nonreceptor) tyr kinase containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. To inhibit Src kinases that are anchored to the plasma membrane, Chk is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. Studies in mice reveal that Chk is not functionally redundant with Csk and that it plays an important role as a regulator of immune responses. Chk also plays a role in neural differentiation in a manner independent of Src by enhancing Mapk activation via Ras-mediated signaling. The Chk 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 767973837 193 WSVELQELPelcfSQQVIREGGHAVVWAGQLQGKLVAIKAFPPRSVAQ-FQAERALyeLPGLQHDHIVRFItasrggpGR 271
Cdd:cd05083    1 WLLNLQKLT----LGEIIGEGEFGAVLQGEYMGQKVAVKNIKCDVTAQaFLEETAV--MTKLQHKNLVRLL-------GV 67