Death Domain of Receptor-Interacting Protein 1; Death domain (DD) found in Receptor-Interacting Protein 1 (RIP1) and related proteins. 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. RIP1 harbors a C-terminal 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 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 accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. In general, 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 CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913 375 TDEHLNPIRENLGRQWKNCARKLGFTESQIDEIDHDYERDGLKEKVYQMLQKWLMREGTKGATVGKLAQALHQCCRIDLL 454
Cdd:cd08777     1 TEKHLDLLRENLGKKWKRCARRLGLTEVEIEEIDHDYERDGLKEKVHQMLEKWKMKEGSKGATVGKLAKALEGCIKSDLL 80

                  ....*.
gi 1720374913 455 NHLIRA 460
Cdd:cd08777    81 VSLLQV 86

RIP homotypic interaction motif; RIP proteins are receptor-interacting serine/threonine-protein kinases or cell death proteins. This interacting domain is involved in virus recognition. The RHIM domain is necessary for the recruitment of RIP and RIP3 by the IFN-inducible protein DNA-dependent activator of IRFs (DAI), also known as DLM-1 or Z-DNA binding protein (ZBP1). Both the RIP kinases contribute to DAI-induced NF-kappaB activation. RIP3 undergoes auto phosphorylation on binding to DAI.

                          10
                  ....*....|....*..
gi 1720374913 327 YTIFNSSGIQIGNHNYM 343
Cdd:pfam12721   3 VIINNCSGVQIGNNNHM 19

Death Domain of Receptor-Interacting Protein 1; Death domain (DD) found in Receptor-Interacting Protein 1 (RIP1) and related proteins. 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. RIP1 harbors a C-terminal 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 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 accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. In general, 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 CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913 375 TDEHLNPIRENLGRQWKNCARKLGFTESQIDEIDHDYERDGLKEKVYQMLQKWLMREGTKGATVGKLAQALHQCCRIDLL 454
Cdd:cd08777     1 TEKHLDLLRENLGKKWKRCARRLGLTEVEIEEIDHDYERDGLKEKVHQMLEKWKMKEGSKGATVGKLAKALEGCIKSDLL 80

                  ....*.
gi 1720374913 455 NHLIRA 460
Cdd:cd08777    81 VSLLQV 86

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 1720374913    1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFAK-KEPYENVIcTEQFVICIKSGNRPnveEILEYCPREIISLMERCWQAI 79
Cdd:smart00221 171 MAPESLKE--GKFTSKSDVWSFGVLLWEIFTLgEEPYPGMS-NAEVLEYLKKGYRL---PKPPNCPPELYKLMLQCWAED 244

                           90
                   ....*....|....
gi 1720374913   80 PEDRPTFLGIEEEF 93
Cdd:smart00221 245 PEDRPTFSELVEIL 258

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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFAK-KEPYENVIcTEQFVICIKSGNRPnveEILEYCPREIISLMERCWQAI 79
Cdd:pfam07714 171 MAPESLKD--GKFTSKSDVWSFGVLLWEIFTLgEQPYPGMS-NEEVLEFLEDGYRL---PQPENCPDELYDLMKQCWAYD 244

                          90
                  ....*....|....
gi 1720374913  80 PEDRPTFLGIEEEF 93
Cdd:pfam07714 245 PEDRPTFSELVEDL 258

hypothetical protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913   3 PEHLNDINAKPTEKSDVYSFGIVLWAIFAKKEPYENVICTEQFVICIKSgnrpNVEEILEY-CPREIISLMERCWQAIPE 81
Cdd:PHA02988  189 YKMLNDIFSEYTIKDDIYSLGVVLWEIFTGKIPFENLTTKEIYDLIINK----NNSLKLPLdCPLEIKCIVEACTSHDSI 264

                  ....
gi 1720374913  82 DRPT 85
Cdd:PHA02988  265 KRPN 268

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFAKKEPYEnVICTEQFVICIKSGNRPNVEEILEYCPREIISLMERCWQAIP 80
Cdd:COG0515   175 MAPEQARG--EPVDPRSDVYSLGVTLYELLTGRPPFD-GDSPAELLRAHLREPPPPPSELRPDLPPALDAIVLRALAKDP 251

                  ....
gi 1720374913  81 EDRP 84
Cdd:COG0515   252 EERY 255

Death Domain of Receptor-Interacting Protein 1; Death domain (DD) found in Receptor-Interacting Protein 1 (RIP1) and related proteins. 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. RIP1 harbors a C-terminal 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 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 accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. In general, 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 CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913 375 TDEHLNPIRENLGRQWKNCARKLGFTESQIDEIDHDYERDGLKEKVYQMLQKWLMREGTKGATVGKLAQALHQCCRIDLL 454
Cdd:cd08777     1 TEKHLDLLRENLGKKWKRCARRLGLTEVEIEEIDHDYERDGLKEKVHQMLEKWKMKEGSKGATVGKLAKALEGCIKSDLL 80

                  ....*.
gi 1720374913 455 NHLIRA 460
Cdd:cd08777    81 VSLLQV 86

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 1720374913   1 MAPEHLNDINAKPTEKSDVYSFGIVLWAIFAKKEPYENVICTEQFVICIKSGNRPNVEEILEYC----PREIISLMERCW 76
Cdd:cd13978   167 MAPEAFDDFNKKPTSKSDVYSFAIVIWAVLTRKEPFENAINPLLIMQIVSKGDRPSLDDIGRLKqienVQELISLMIRCW 246

                          90
                  ....*....|....*....
gi 1720374913  77 QAIPEDRPTFLgiEEEFRP 95
Cdd:cd13978   247 DGNPDARPTFL--ECLDRL 263

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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFAK-KEPYENVIcTEQFVICIKSGNRPnveEILEYCPREIISLMERCWQAI 79
Cdd:cd00192   174 MAPESLKD--GIFTSKSDVWSFGVLLWEIFTLgATPYPGLS-NEEVLEYLRKGYRL---PKPENCPDELYELMLSCWQLD 247

                          90
                  ....*....|....*
gi 1720374913  80 PEDRPTFLGIEEEFR 94
Cdd:cd00192   248 PEDRPTFSELVERLE 262

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913    1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFAK-KEPYENVIcTEQFVICIKSGNRPnveEILEYCPREIISLMERCWQAI 79
Cdd:smart00219 170 MAPESLKE--GKFTSKSDVWSFGVLLWEIFTLgEQPYPGMS-NEEVLEYLKNGYRL---PQPPNCPPELYDLMLQCWAED 243

                           90
                   ....*....|....
gi 1720374913   80 PEDRPTFLGIEEEF 93
Cdd:smart00219 244 PEDRPTFSELVEIL 257

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 1720374913   1 MAPEHlndINAKP-TEKSDVYSFGIVLWAIFAKKEPYENVictEQFVICIKSGNRPNVEEILEYCPREIISLMERCWQAI 79
Cdd:cd13999   158 MAPEV---LRGEPyTEKADVYSFGIVLWELLTGEVPFKEL---SPIQIAAAVVQKGLRPPIPPDCPPELSKLIKRCWNED 231

                          90
                  ....*....|....
gi 1720374913  80 PEDRPTFLGIEEEF 93
Cdd:cd13999   232 PEKRPSFSEIVKRL 245

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913  372 TSLTDEHLNPIREN-LGRQWKNCARKLGFTESQIDEIDHDYERDgLKEKVYQMLQKWLMREGtKGATVGKLAQALHQCCR 450
Cdd:smart00005   1 PELTRQKLAKLLDHpLGLDWRELARKLGLSEADIDQIRTEAPRD-LAEQSVQLLRLWEQREG-KNATLGTLLEALRKMGR 78

                   ....
gi 1720374913  451 IDLL 454
Cdd:smart00005  79 DDAV 82

Fas-associated Death Domain protein-protein interaction domain; Death domain (DD) found in FAS-associated via death domain (FADD). FADD is a component of the death-inducing signaling complex (DISC) and serves as an adaptor in the signaling pathway of death receptor proteins. It modulates apoptosis as well as non-apoptotic processes such as cell cycle progression, survival, innate immune signaling, and hematopoiesis. FADD contains an N-terminal DED and a C-terminal DD. Its DD interacts with the DD of the activated death receptor, FAS, and its DED recruits the initiator caspases, caspase-8 and -10, to the DISC complex via a homotypic interaction with the N-terminal DED of the caspase. 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 CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1720374913 382 IRENLGRQWKNCARKLGFTESQIDEIDHDYERDgLKEKVYQMLQKWLMREGtKGATVGKLAQALHQC 448
Cdd:cd08306     8 ICENLGRDWRQLARKLGLSETKIESISEAHPRN-LREQVRQSLREWKKIKK-AEATVADLIKALRDC 72

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEQFVIcIKSGNR----PNveeileyCPREIISLMERC 75
Cdd:cd05099   203 MAPEALFD--RVYTHQSDVWSFGILMWEIFTlGGSPYPGIPVEELFKL-LREGHRmdkpSN-------CTHELYMLMREC 272

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1720374913  76 WQAIPEDRPTFLGIEEEFRPFYLSHFEEYVE 106
Cdd:cd05099   273 WHAVPTQRPTFKQLVEALDKVLAAVSEEYLD 303

Catalytic domain of the Protein Tyrosine Kinases, Discoidin Domain Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The DDR subfamily consists of homologs of mammalian DDR1, DDR2, and similar proteins. They are receptor PTKs (RTKs) containing an extracellular discoidin homology domain, a transmembrane segment, an extended juxtamembrane region, and an intracellular catalytic domain. The binding of the ligand, collagen, to DDRs results in a slow but sustained receptor activation. DDRs regulate cell adhesion, proliferation, and extracellular matrix remodeling. They have been linked to a variety of human cancers including breast, colon, ovarian, brain, and lung. There is no evidence showing that DDRs act as transforming oncogenes. They are more likely to play a role in the regulation of tumor growth and metastasis. The DDR 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 1720374913  12 KPTEKSDVYSFGIVLWAI--FAKKEPYEnVICTEQfVI--CIKSGNRPNVEEILEY---CPREIISLMERCWQAIPEDRP 84
Cdd:cd05051   209 KFTTKSDVWAFGVTLWEIltLCKEQPYE-HLTDEQ-VIenAGEFFRDDGMEVYLSRppnCPKEIYELMLECWRRDEEDRP 286

                  ..
gi 1720374913  85 TF 86
Cdd:cd05051   287 TF 288

Catalytic domain of Insulin Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The InsR subfamily is composed of InsR, Insulin-like Growth Factor-1 Receptor (IGF-1R), and similar proteins. InsR and IGF-1R are receptor PTKs (RTKs) composed of two alphabeta heterodimers. Binding of the ligand (insulin, IGF-1, or IGF-2) 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 and IGF-1R, which share 84% sequence identity in their kinase domains, display physiologically distinct yet overlapping functions in cell growth, differentiation, and metabolism. InsR activation leads primarily to metabolic effects while IGF-1R activation stimulates mitogenic pathways. In cells expressing both receptors, InsR/IGF-1R hybrids are found together with classical receptors. Both receptors can interact with common adaptor molecules such as IRS-1 and IRS-2. The InsR-like subfamily 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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAI--FAKkEPY-----ENVIcteQFVICIKSGNRPnveeilEYCPREIISLME 73
Cdd:cd05032   188 MAPESLKD--GVFTTKSDVWSFGVVLWEMatLAE-QPYqglsnEEVL---KFVIDGGHLDLP------ENCPDKLLELMR 255

                          90
                  ....*....|....*.
gi 1720374913  74 RCWQAIPEDRPTFLGI 89
Cdd:cd05032   256 MCWQYNPKMRPTFLEI 271

Catalytic domain of C-terminal Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of Csk, Chk, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, Csk and Chk are translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. Csk catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. Chk inhibit Src kinases using a noncatalytic mechanism by simply binding to them. As negative regulators of Src kinases, Csk and Chk play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. The Csk-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 1720374913   2 APEHLNdiNAKPTEKSDVYSFGIVLWAIFA-KKEPYENvICTEQFVICIKSGNRpnvEEILEYCPREIISLMERCWQAIP 80
Cdd:cd05039   167 APEALR--EKKFSTKSDVWSFGILLWEIYSfGRVPYPR-IPLKDVVPHVEKGYR---MEAPEGCPPEVYKVMKNCWELDP 240

                          90
                  ....*....|..
gi 1720374913  81 EDRPTFLGIEEE 92
Cdd:cd05039   241 AKRPTFKQLREK 252

Catalytic domain of the Protein Tyrosine Kinases, Vascular Endothelial Growth Factor Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The VEGFR subfamily consists of VEGFR1 (Flt1), VEGFR2 (Flk1), VEGFR3 (Flt4), and similar proteins. VEGFR subfamily members are receptor PTKss (RTKs) containing an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and an intracellular catalytic domain. In VEGFR3, the fifth Ig-like domain is replaced by a disulfide bridge. The binding of VEGFRs to their ligands, the VEGFs, leads to receptor dimerization, activation, and intracellular signaling. There are five VEGF ligands in mammals, which bind, in an overlapping pattern to the three VEGFRs, which can form homo or heterodimers. VEGFRs regulate the cardiovascular system. They are critical for vascular development during embryogenesis and blood vessel formation in adults. They induce cellular functions common to other growth factor receptors such as cell migration, survival, and proliferation. The VEGFR 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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEQFVICIKSGNRPNVEEileYCPREIISLMERCWQAI 79
Cdd:cd05054   207 MAPESIFD--KVYTTQSDVWSFGVLLWEIFSlGASPYPGVQMDEEFCRRLKEGTRMRAPE---YTTPEIYQIMLDCWHGE 281

                          90
                  ....*....|...
gi 1720374913  80 PEDRPTFLGIEEE 92
Cdd:cd05054   282 PKERPTFSELVEK 294

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 1720374913   1 MAPEHlndINAKPT-EKSDVYSFGIVLWAIFAKKEPYENVICTEQFVICIKSGNRPNveeILEYCPREIISLMERCWQAI 79
Cdd:cd14060   152 MAPEV---IQSLPVsETCDTYSYGVVLWEMLTREVPFKGLEGLQVAWLVVEKNERPT---IPSSCPRSFAELMRRCWEAD 225

                          90
                  ....*....|
gi 1720374913  80 PEDRPTFLGI 89
Cdd:cd14060   226 VKERPSFKQI 235

Catalytic domain of Fes-like Protein Tyrosine Kinases; Protein Tyrosine Kinase (PTK) family; Fes subfamily; catalytic (c) domain. Fes subfamily members include Fes (or Fps), Fer, and similar proteins. The PTKc family is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, and phosphoinositide 3-kinase (PI3K). PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Fes subfamily proteins are cytoplasmic (or nonreceptor) tyr kinases containing an N-terminal region with FCH (Fes/Fer/CIP4 homology) and coiled-coil domains, followed by a SH2 domain, and a C-terminal catalytic domain. The genes for Fes (feline sarcoma) and Fps (Fujinami poultry sarcoma) were first isolated from tumor-causing retroviruses. The viral oncogenes encode chimeric Fes proteins consisting of Gag sequences at the N-termini, resulting in unregulated tyr kinase activity. Fes and Fer kinases play roles in haematopoiesis, inflammation and immunity, growth factor signaling, cytoskeletal regulation, cell migration and adhesion, and the regulation of cell-cell interactions. Fes and Fer show redundancy in their biological functions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720374913   2 APEHLNdiNAKPTEKSDVYSFGIVLWAIFAKKE-PYENvICTEQFVICIKSGNR---PnveeilEYCPREIISLMERCWQ 77
Cdd:cd05041   164 APEALN--YGRYTSESDVWSFGILLWEIFSLGAtPYPG-MSNQQTREQIESGYRmpaP------ELCPEAVYRLMLQCWA 234

                          90
                  ....*....|....*
gi 1720374913  78 AIPEDRPTFLGIEEE 92
Cdd:cd05041   235 YDPENRPSFSEIYNE 249

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 1720374913   2 APEHLNdiNAKPTEKSDVYSFGIVLWAIFAKKE-PYENvICTEQFVICIKSGNRPNVEEIleyCPREIISLMERCWQAIP 80
Cdd:cd05060   166 APECIN--YGKFSSKSDVWSYGVTLWEAFSYGAkPYGE-MKGPEVIAMLESGERLPRPEE---CPQEIYSIMLSCWKYRP 239

                          90
                  ....*....|....*..
gi 1720374913  81 EDRPTFLGIEEEFRPFY 97
Cdd:cd05060   240 EDRPTFSELESTFRRDP 256

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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFAKKE-PYENvICTEQFVICIKSG---NRPnveeilEYCPREIISLMERCW 76
Cdd:cd05061   188 MAPESLKD--GVFTTSSDMWSFGVVLWEITSLAEqPYQG-LSNEQVLKFVMDGgylDQP------DNCPERVTDLMRMCW 258

                          90       100
                  ....*....|....*....|....*..
gi 1720374913  77 QAIPEDRPTFLGIEEEFRPFYLSHFEE 103
Cdd:cd05061   259 QFNPKMRPTFLEIVNLLKDDLHPSFPE 285

Catalytic domain of the Protein Tyrosine Kinase, Platelet Derived Growth Factor Receptor alpha; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. PDGFR alpha is a receptor PTK (RTK) containing an extracellular ligand-binding region with five immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. The binding to its ligands, the PDGFs, leads to receptor dimerization, trans phosphorylation and activation, and intracellular signaling. PDGFR alpha forms homodimers or heterodimers with PDGFR beta, depending on the nature of the PDGF ligand. PDGF-AA, PDGF-AB, and PDGF-CC induce PDGFR alpha homodimerization. PDGFR signaling plays many roles in normal embryonic development and adult physiology. PDGFR alpha signaling is important in the formation of lung alveoli, intestinal villi, mesenchymal dermis, and hair follicles, as well as in the development of oligodendrocytes, retinal astrocytes, neural crest cells, and testicular cells. Aberrant PDGFR alpha expression is associated with some human cancers. Mutations in PDGFR alpha have been found within a subset of gastrointestinal stromal tumors (GISTs). An active fusion protein FIP1L1-PDGFR alpha, derived from interstitial deletion, is associated with idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia. The PDGFR alpha 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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEQFVICIKSGNRPNVEEileYCPREIISLMERCWQAI 79
Cdd:cd05105   306 MAPESIFD--NLYTTLSDVWSYGILLWEIFSlGGTPYPGMIVDSTFYNKIKSGYRMAKPD---HATQEVYDIMVKCWNSE 380

                          90
                  ....*....|..
gi 1720374913  80 PEDRPTFLGIEE 91
Cdd:cd05105   381 PEKRPSFLHLSD 392

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 1720374913   2 APEHLNdiNAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEqFVICIKSGNRpnvEEILEYCPREIISLMERCWQAIP 80
Cdd:cd05083   165 APEALK--NKKFSSKSDVWSYGVLLWEVFSyGRAPYPKMSVKE-VKEAVEKGYR---MEPPEGCPPDVYSIMTSCWEAEP 238

                          90
                  ....*....|...
gi 1720374913  81 EDRPTFLGIEEEF 93
Cdd:cd05083   239 GKRPSFKKLREKL 251

Catalytic domain of the Protein Tyrosine Kinase, Vascular Endothelial Growth Factor Receptor 3; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. VEGFR3 (or Flt4) preferentially binds the ligands VEGFC and VEGFD. VEGFR3 is essential for lymphatic endothelial cell (EC) development and function. It has been shown to regulate adaptive immunity during corneal transplantation. VEGFR3 is upregulated on blood vascular ECs in pathological conditions such as vascular tumors and the periphery of solid tumors. It plays a role in cancer progression and lymph node metastasis. Missense mutations in the VEGFR3 gene are associated with primary human lymphedema. VEGFR3 is a member of the VEGFR subfamily of proteins, which are receptor PTKs (RTKs) containing an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and an intracellular catalytic domain. In VEGFR3, the fifth Ig-like domain is replaced by a disulfide bridge. The binding of VEGFRs to their ligands, the VEGFs, leads to receptor dimerization, activation, and intracellular signaling. The VEGFR3 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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEQFVICIKSGNRPNVEEileYCPREIISLMERCWQAI 79
Cdd:cd05102   241 MAPESIFD--KVYTTQSDVWSFGVLLWEIFSlGASPYPGVQINEEFCQRLKDGTRMRAPE---YATPEIYRIMLSCWHGD 315

                          90
                  ....*....|..
gi 1720374913  80 PEDRPTFLGIEE 91
Cdd:cd05102   316 PKERPTFSDLVE 327

Catalytic domain of the Protein Tyrosine Kinase, Zeta-chain-associated protein of 70kDa; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Zap-70 is a cytoplasmic (or nonreceptor) PTK containing two Src homology 2 (SH2) domains N-terminal to the catalytic tyr kinase domain. Zap-70 is primarily expressed in T-cells and NK cells, and is a crucial component in T-cell receptor (TCR) signaling. Zap-70 binds the phosphorylated ITAM (immunoreceptor tyr activation motif) sequences of the activated TCR zeta-chain through its SH2 domains, leading to its phosphorylation and activation. It then phosphorylates target proteins, which propagate the signals to downstream pathways. Zap-70 is hardly detected in normal peripheral B-cells, but is present in some B-cell malignancies. It is used as a diagnostic marker for chronic lymphocytic leukemia (CLL) as it is associated with the more aggressive subtype of the disease. The Zap-70 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 1720374913   2 APEHLNdiNAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEqFVICIKSGNRpnvEEILEYCPREIISLMERCWQAIP 80
Cdd:cd05115   175 APECIN--FRKFSSRSDVWSYGVTMWEAFSyGQKPYKKMKGPE-VMSFIEQGKR---MDCPAECPPEMYALMSDCWIYKW 248

                          90
                  ....*....|....*....
gi 1720374913  81 EDRPTFLGIEEEFRPFYLS 99
Cdd:cd05115   249 EDRPNFLTVEQRMRTYYYS 267

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 1720374913   2 APEHLNdiNAKPTEKSDVYSFGIVLWAIFAK-KEPYENVICTEQfviciksgnrpnVEEILE--------YCPREIISLM 72
Cdd:cd05059   169 PPEVFM--YSKFSSKSDVWSFGVLMWEVFSEgKMPYERFSNSEV------------VEHISQgyrlyrphLAPTEVYTIM 234

                          90
                  ....*....|....
gi 1720374913  73 ERCWQAIPEDRPTF 86
Cdd:cd05059   235 YSCWHEKPEERPTF 248

Catalytic domain of the Protein Tyrosine Kinases, Anaplastic Lymphoma Kinase and Leukocyte Tyrosine Kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyr residues in protein substrates. ALK and LTK are orphan receptor PTKs (RTKs) whose ligands are not yet well-defined. ALK appears to play an important role in mammalian neural development as well as visceral muscle differentiation in Drosophila. ALK is aberrantly expressed as fusion proteins, due to chromosomal translocations, in about 60% of anaplastic large cell lymphomas (ALCLs). ALK fusion proteins are also found in rare cases of diffuse large B cell lymphomas (DLBCLs). LTK is mainly expressed in B lymphocytes and neuronal tissues. It is important in cell proliferation and survival. Transgenic mice expressing TLK display retarded growth and high mortality rate. In addition, a polymorphism in mouse and human LTK is implicated in the pathogenesis of systemic lupus erythematosus. RTKs contain an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyr kinase domain. They are usually activated through ligand binding, which causes dimerization and autophosphorylation of the intracellular tyr kinase catalytic domain. The ALK/LTK 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 1720374913  14 TEKSDVYSFGIVLWAIFA-KKEPYENVICTE--QFVIcikSGNR---PNveeileYCPREIISLMERCWQAIPEDRPTFL 87
Cdd:cd05036   199 TSKTDVWSFGVLLWEIFSlGYMPYPGKSNQEvmEFVT---SGGRmdpPK------NCPGPVYRIMTQCWQHIPEDRPNFS 269

                  ....
gi 1720374913  88 GIEE 91
Cdd:cd05036   270 TILE 273

Catalytic domain of the Protein Tyrosine Kinase, Fibroblast Growth Factor Receptor 3; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Many FGFR3 splice variants have been reported with the IIIb and IIIc isoforms being the predominant forms. FGFR3 IIIc is the isoform expressed in chondrocytes, the cells affected in dwarfism, while IIIb is expressed in epithelial cells. FGFR3 ligands include FGF1, FGF2, FGF4, FGF8, FGF9, and FGF23. It is a negative regulator of long bone growth. In the cochlear duct and in the lens, FGFR3 is involved in differentiation while it appears to have a role in cell proliferation in epithelial cells. Germline mutations in FGFR3 are associated with skeletal disorders including several forms of dwarfism. Some missense mutations are associated with multiple myeloma and carcinomas of the bladder and cervix. Overexpression of FGFR3 is found in thyroid carcinoma. FGFR3 is part of the FGFR subfamily, which are receptor PTKs (RTKs) containing an extracellular ligand-binding region with three immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. The binding of FGFRs to their ligands, the FGFs, results in receptor dimerization and activation, and intracellular signaling. The binding of FGFs to FGFRs is promiscuous, in that a receptor may be activated by several ligands and a ligand may bind to more that one type of receptor. The FGFR3 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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEQFVIcIKSGNRPNVEEileYCPREIISLMERCWQAI 79
Cdd:cd05100   203 MAPEALFD--RVYTHQSDVWSFGVLLWEIFTlGGSPYPGIPVEELFKL-LKEGHRMDKPA---NCTHELYMIMRECWHAV 276

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1720374913  80 PEDRPTFLGIEEEF-RPFYLSHFEEYVEEDV 109
Cdd:cd05100   277 PSQRPTFKQLVEDLdRVLTVTSTDEYLDLSV 307

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 1720374913   1 MAPEHLNdiNAKPTEKSDVYSFGIVLWAIFAKKEPYENVictEQFVI--CIKSGNRPNVEEILEYCPREII-SLMERCWQ 77
Cdd:cd13979   173 RAPELLK--GERVTPKADIYSFGITLWQMLTRELPYAGL---RQHVLyaVVAKDLRPDLSGLEDSEFGQRLrSLISRCWS 247

                  ....*...
gi 1720374913  78 AIPEDRPT 85
Cdd:cd13979   248 AQPAERPN 255

Catalytic domain of the Protein Tyrosine Kinase, Vascular Endothelial Growth Factor Receptor 2; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. VEGFR2 (or Flk1) binds the ligands VEGFA, VEGFC, VEGFD and VEGFE. VEGFR2 signaling is implicated in all aspects of normal and pathological vascular endothelial cell biology. It induces a variety of cellular effects including migration, survival, and proliferation. It is critical in regulating embryonic vascular development and angiogenesis. VEGFR2 is the major signal transducer in pathological angiogenesis including cancer and diabetic retinopathy, and is a target for inhibition in cancer therapy. The carboxyl terminus of VEGFR2 plays an important role in its autophosphorylation and activation. VEGFR2 is a member of the VEGFR subfamily of proteins, which are receptor PTKs (RTKs) containing an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and an intracellular catalytic domain. The binding of VEGFRs to their ligands, the VEGFs, leads to receptor dimerization, activation, and intracellular signaling. The VEGFR2 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 1720374913   1 MAPEHLNDinAKPTEKSDVYSFGIVLWAIFA-KKEPYENVICTEQFVICIKSGNRPNVEeilEYCPREIISLMERCWQAI 79
Cdd:cd05103   248 MAPETIFD--RVYTIQSDVWSFGVLLWEIFSlGASPYPGVKIDEEFCRRLKEGTRMRAP---DYTTPEMYQTMLDCWHGE 322