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 1238280194   1 MWSKLNNEEHNELREVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKS 80
Cdd:cd14027   141 MWSKLTKEEHNEQREVDGTAKKNAGTLYYMAPEHLNDVNAKPTEKSDVYSFAIVLWAIFANKEPYENAINEDQIIMCIKS 220

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1238280194  81 GNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYL 127
Cdd:cd14027   221 GNRPDVDDITEYCPREIIDLMKLCWEANPEARPTFPGIEEKFRPFYL 267

Catalytic domain of the Serine/Threonine kinase, Receptor Interacting Protein 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RIP1 harbors a C-terminal Death domain (DD), which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 can also recruit other kinases including MEKK1, MEKK3, and RIP3 through an intermediate domain (ID) that bears a RIP homotypic interaction motif (RHIM). RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accummulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. RIP kinases serve as essential sensors of cellular stress. The RIP1 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194   1 MWSKLNNEEHNELREVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKS 80
Cdd:cd14027   141 MWSKLTKEEHNEQREVDGTAKKNAGTLYYMAPEHLNDVNAKPTEKSDVYSFAIVLWAIFANKEPYENAINEDQIIMCIKS 220

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1238280194  81 GNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYL 127
Cdd:cd14027   221 GNRPDVDDITEYCPREIIDLMKLCWEANPEARPTFPGIEEKFRPFYL 267

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194 421 DKHLDPIREN---LGKHWKNCARKLGFTQSQIDEIDHDYERdgLKEKVYQMLQKWVMREGiKGATVGKLAQALHQCSRID 497
Cdd:pfam00531   1 RKQLDRLLDPpppLGKDWRELARKLGLSENEIDEIESENPR--LRSQTYELLRLWEQREG-KNATVGTLLEALRKLGRRD 77

                  ....*..
gi 1238280194 498 LLSSLIY 504
Cdd:pfam00531  78 AAEKIQS 84

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 1238280194  417 TSLTDKHLDPIREN-LGKHWKNCARKLGFTQSQIDEIDHDYERDgLKEKVYQMLQKWVMREGIKgATVGKLAQALHQCSR 495
Cdd:smart00005   1 PELTRQKLAKLLDHpLGLDWRELARKLGLSEADIDQIRTEAPRD-LAEQSVQLLRLWEQREGKN-ATLGTLLEALRKMGR 78

                   ....*....
gi 1238280194  496 IDLLSSLIY 504
Cdd:smart00005  79 DDAVELLRS 87

hypothetical protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194  22 KNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGNRPDVDditEYCPREIISLM 101
Cdd:PHA02988  179 KNVNFMVYFSYKMLNDIFSEYTIKDDIYSLGVVLWEIFTGKIPFENLTTKEIYDLIINKNNSLKLP---LDCPLEIKCIV 255

                          90       100
                  ....*....|....*....|....*
gi 1238280194 102 KLCWEANPEARPTFPGIEEKFRPFY 126
Cdd:PHA02988  256 EACTSHDSIKRPNIKEILYNLSLYK 280

Catalytic domain of the Serine/Threonine kinase, Receptor Interacting Protein 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. RIP1 harbors a C-terminal Death domain (DD), which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 can also recruit other kinases including MEKK1, MEKK3, and RIP3 through an intermediate domain (ID) that bears a RIP homotypic interaction motif (RHIM). RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accummulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. RIP kinases serve as essential sensors of cellular stress. The RIP1 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194   1 MWSKLNNEEHNELREVDGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKS 80
Cdd:cd14027   141 MWSKLTKEEHNEQREVDGTAKKNAGTLYYMAPEHLNDVNAKPTEKSDVYSFAIVLWAIFANKEPYENAINEDQIIMCIKS 220

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1238280194  81 GNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYL 127
Cdd:cd14027   221 GNRPDVDDITEYCPREIIDLMKLCWEANPEARPTFPGIEEKFRPFYL 267

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 1238280194   1 MWSKLNNEEhnelrevdGTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAIcEQQLIMCIKS 80
Cdd:cd13978   146 MKSISANRR--------RGTENLGGTPIYMAPEAFDDFNKKPTSKSDVYSFAIVIWAVLTRKEPFENAI-NPLLIMQIVS 216

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1238280194  81 -GNRPDVDDITEYC----PREIISLMKLCWEANPEARPTFpgIEEKFRP 124
Cdd:cd13978   217 kGDRPSLDDIGRLKqienVQELISLMIRCWDGNPDARPTF--LECLDRL 263

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 1238280194  25 GTLYYMAPEHLNDVNAkpTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGNRPdvdDITEYCPREIISLMKLC 104
Cdd:cd13999   153 GTPRWMAPEVLRGEPY--TEKADVYSFGIVLWELLTGEVPFKELSPIQIAAAVVQKGLRP---PIPPDCPPELSKLIKRC 227

                          90
                  ....*....|....*...
gi 1238280194 105 WEANPEARPTFPGIEEKF 122
Cdd:cd13999   228 WNEDPEKRPSFSEIVKRL 245

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194   4 KLNNEEHNELREVDGTAKKNGGT----LYYMAPEHL--NDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC 77
Cdd:cd13992   138 KLTDFGLRNLLEEQTNHQLDEDAqhkkLLWTAPELLrgSLLEVRGTQKGDVYSFAIILYEILFRSDPFALEREVAIVEKV 217

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1238280194  78 IKSGN---RPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPF 125
Cdd:cd13992   218 ISGGNkpfRPELAVLLDEFPPRLVLLVKQCWAENPEKRPSFKQIKKTLTEN 268

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 1238280194   29 YMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFAN-KEPYENAICeQQLIMCIKSGNRPDvddITEYCPREIISLMKLCWEA 107
Cdd:smart00221 170 WMAPESLKE--GKFTSKSDVWSFGVLLWEIFTLgEEPYPGMSN-AEVLEYLKKGYRLP---KPPNCPPELYKLMLQCWAE 243

                           90
                   ....*....|....*
gi 1238280194  108 NPEARPTFPGIEEKF 122
Cdd:smart00221 244 DPEDRPTFSELVEIL 258

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194   29 YMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFAN-KEPYENAICeQQLIMCIKSGNRPDvddITEYCPREIISLMKLCWEA 107
Cdd:smart00219 169 WMAPESLKE--GKFTSKSDVWSFGVLLWEIFTLgEQPYPGMSN-EEVLEYLKNGYRLP---QPPNCPPELYDLMLQCWAE 242

                           90
                   ....*....|....*
gi 1238280194  108 NPEARPTFPGIEEKF 122
Cdd:smart00219 243 DPEDRPTFSELVEIL 257

Catalytic domain of the Serine/Threonine kinases, Receptor Interacting Protein 4 and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of RIP4, ankyrin (ANK) repeat and kinase domain containing 1 (ANKK1), and similar proteins, all of which harbor C-terminal ANK repeats. RIP4, also called Protein Kinase C-associated kinase (PKK), regulates keratinocyte differentiation and cutaneous inflammation. It activates NF-kappaB and is important in the survival of diffuse large B-cell lymphoma cells. The ANKK1 protein, also called PKK2, has not been studied extensively. The ANKK1 gene, located less than 10kb downstream of the D2 dopamine receptor (DRD2) locus, is altered in the Taq1 A1 polymorphism, which is related to a reduced DRD2 binding affinity and consequently, to mental disorders. The RIP4-like subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194   3 SKLNNEEHNELREVDGTAkkngGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGN 82
Cdd:cd14025   141 AKWNGLSHSHDLSRDGLR----GTIAYLPPERFKEKNRCPDTKHDVYSFAIVIWGILTQKKPFAGENNILHIMVKVVKGH 216

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1238280194  83 RPDVDDITEYCPRE---IISLMKLCWEANPEARPTFPGI 118
Cdd:cd14025   217 RPSLSPIPRQRPSEcqqMICLMKRCWDQDPRKRPTFQDI 255

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 1238280194  11 NELREVDGTAKKNGGTLYYMAPEHLNdvNAKPTEKSDVYSFAVVLWAIFANKEPYEnAICEQQLIMCIKSGNRPDVDDIT 90
Cdd:cd13979   154 GEGNEVGTPRSHIGGTYTYRAPELLK--GERVTPKADIYSFGITLWQMLTRELPYA-GLRQHVLYAVVAKDLRPDLSGLE 230

                          90       100
                  ....*....|....*....|....*
gi 1238280194  91 EYCPREII-SLMKLCWEANPEARPT 114
Cdd:cd13979   231 DSEFGQRLrSLISRCWSAQPAERPN 255

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194  27 LYYMAPEHL--NDVNAKPTEKSDVYSFAVVLWAIFANKEPYENA--------ICEQQLIMCIKSGNRPDVDDITeyCPRE 96
Cdd:cd14042   170 LLWTAPELLrdPNPPPPGTQKGDVYSFGIILQEIATRQGPFYEEgpdlspkeIIKKKVRNGEKPPFRPSLDELE--CPDE 247

                          90       100
                  ....*....|....*....|....*....
gi 1238280194  97 IISLMKLCWEANPEARPTFPGIEEKFRPF 125
Cdd:cd14042   248 VLSLMQRCWAEDPEERPDFSTLRNKLKKL 276

Catalytic domain of the Serine/Threonine Kinases, Raf (Rapidly Accelerated Fibrosarcoma) kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Raf kinases act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. They function in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. Aberrant expression or activation of components in this pathway are associated with tumor initiation, progression, and metastasis. Raf proteins contain a Ras binding domain, a zinc finger cysteine-rich domain, and a catalytic kinase domain. Vertebrates have three Raf isoforms (A-, B-, and C-Raf) with different expression profiles, modes of regulation, and abilities to function in the ERK cascade, depending on cellular context and stimuli. They have essential and non-overlapping roles during embryo- and organogenesis. Knockout of each isoform results in a lethal phenotype or abnormality in most mouse strains. The Raf subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194  25 GTLYYMAPEHLNDVNAKP-TEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGN-RPDVDDITEYCPREIISLMK 102
Cdd:cd14062   153 GSILWMAPEVIRMQDENPySFQSDVYAFGIVLYELLTGQLPYSHINNRDQILFMVGRGYlRPDLSKVRSDTPKALRRLME 232

                          90
                  ....*....|....*.
gi 1238280194 103 LCWEANPEARPTFPGI 118
Cdd:cd14062   233 DCIKFQRDERPLFPQI 248

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 1238280194  12 ELREVDGTAKKNGGTL--YYMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFANKE-PYENAICEQQLIMCIKSG--NRPdv 86
Cdd:cd05061   168 DIYETDYYRKGGKGLLpvRWMAPESLKD--GVFTTSSDMWSFGVVLWEITSLAEqPYQGLSNEQVLKFVMDGGylDQP-- 243

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1238280194  87 dditEYCPREIISLMKLCWEANPEARPTFPGIEEKFR 123
Cdd:cd05061   244 ----DNCPERVTDLMRMCWQFNPKMRPTFLEIVNLLK 276

Catalytic domain of the Protein Tyrosine Kinase, Spleen tyrosine kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Syk is a cytoplasmic (or nonreceptor) PTK containing two Src homology 2 (SH2) domains N-terminal to the catalytic tyr kinase domain. Syk was first cloned from the spleen, and its function in hematopoietic cells is well-established. It is involved in the signaling downstream of activated receptors (including B-cell and Fc receptors) that contain ITAMs (immunoreceptor tyr activation motifs), leading to processes such as cell proliferation, differentiation, survival, adhesion, migration, and phagocytosis. More recently, Syk expression has been detected in other cell types (including epithelial cells, vascular endothelial cells, neurons, hepatocytes, and melanocytes), suggesting a variety of biological functions in non-immune cells. Syk plays a critical role in maintaining vascular integrity and in wound healing during embryogenesis. It also regulates Vav3, which is important in osteoclast function including bone development. In breast epithelial cells, where Syk acts as a negative regulator for EGFR signaling, loss of Syk expression is associated with abnormal proliferation during cancer development suggesting a potential role as a tumor suppressor. In mice, Syk has been shown to inhibit malignant transformation of mammary epithelial cells induced with murine mammary tumor virus (MMTV). The Syk 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 1238280194  27 LYYMAPEHLNdvNAKPTEKSDVYSFAVVLWAIFA-NKEPYENAICEQQLIMcIKSGNRPDVddiTEYCPREIISLMKLCW 105
Cdd:cd05116   162 VKWYAPECMN--YYKFSSKSDVWSFGVLMWEAFSyGQKPYKGMKGNEVTQM-IEKGERMEC---PAGCPPEMYDLMKLCW 235

                          90       100
                  ....*....|....*....|.
gi 1238280194 106 EANPEARPTFPGIEEKFRPFY 126
Cdd:cd05116   236 TYDVDERPGFAAVELRLRNYY 256

Catalytic domain of the Protein Tyrosine Kinase, C-ros; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily contains c-ros, Sevenless, and similar proteins. The proto-oncogene c-ros encodes an orphan receptor PTK (RTK) with an unknown ligand. RTKs contain an extracellular ligand-binding domain, a transmembrane region, 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. C-ros is expressed in embryonic cells of the kidney, intestine and lung, but disappears soon after birth. It persists only in the adult epididymis. Male mice bearing inactive mutations of c-ros lack the initial segment of the epididymis and are infertile. The Drosophila protein, Sevenless, is required for the specification of the R7 photoreceptor cell during eye development. The c-ros 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 1238280194  29 YMAPEHLndVNAKPTEKSDVYSFAVVLWAIFA-NKEPYEnAICEQQLIMCIKSGNRPDVDDiteYCPREIISLMKLCWEA 107
Cdd:cd05044   178 WMAPESL--VDGVFTTQSDVWAFGVLMWEILTlGQQPYP-ARNNLEVLHFVRAGGRLDQPD---NCPDDLYELMLRCWST 251

                          90
                  ....*....|....
gi 1238280194 108 NPEARPTFPGIEEK 121
Cdd:cd05044   252 DPEERPSFARILEQ 265

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 1238280194  13 LREVDGTAKKNGGTL--YYMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFA-NKEPYEnAICEQQLIMCIKSGNRPDVddi 89
Cdd:cd05099   184 VHDIDYYKKTSNGRLpvKWMAPEALFD--RVYTHQSDVWSFGILMWEIFTlGGSPYP-GIPVEELFKLLREGHRMDK--- 257

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1238280194  90 TEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEE 132
Cdd:cd05099   258 PSNCTHELYMLMRECWHAVPTQRPTFKQLVEALDKVLAAVSEE 300

Catalytic domain of the Protein Tyrosine Kinases, Fibroblast Growth Factor Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The FGFR subfamily consists of FGFR1, FGFR2, FGFR3, FGFR4, and similar proteins. They 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, and to heparin/heparan sulfate (HS) results in the formation of a ternary complex, which leads to receptor dimerization and activation, and intracellular signaling. There are at least 23 FGFs and four types of FGFRs. 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. FGF/FGFR signaling is important in the regulation of embryonic development, homeostasis, and regenerative processes. Depending on the cell type and stage, FGFR signaling produces diverse cellular responses including proliferation, growth arrest, differentiation, and apoptosis. Aberrant signaling leads to many human diseases such as skeletal, olfactory, and metabolic disorders, as well as cancer. The FGFR 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 1238280194  12 ELREVDGTAKKNGGTLYY--MAPEHLNDvnAKPTEKSDVYSFAVVLWAIFA-NKEPYEnAICEQQLIMCIKSGNRPDVdd 88
Cdd:cd05053   182 DIHHIDYYRKTTNGRLPVkwMAPEALFD--RVYTHQSDVWSFGVLLWEIFTlGGSPYP-GIPVEELFKLLKEGHRMEK-- 256

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1238280194  89 iTEYCPREIISLMKLCWEANPEARPTFPGIEE 120
Cdd:cd05053   257 -PQNCTQELYMLMRDCWHEVPSQRPTFKQLVE 287

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 1238280194  27 LYYMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFA-NKEPYENAICEQQLIMCIKSGNR---PdvdditEYCPREIISLMK 102
Cdd:cd05054   204 LKWMAPESIFD--KVYTTQSDVWSFGVLLWEIFSlGASPYPGVQMDEEFCRRLKEGTRmraP------EYTTPEIYQIML 275

                          90
                  ....*....|....*....
gi 1238280194 103 LCWEANPEARPTFPGIEEK 121
Cdd:cd05054   276 DCWHGEPKERPTFSELVEK 294

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194   25 GTLYYMAPEHLNdvNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGNrPDVDDITEYCPREIISLMKLC 104
Cdd:smart00220 158 GTPEYMAPEVLL--GKGYGKAVDIWSLGVILYELLTGKPPFPGDDQLLELFKKIGKPK-PPFPPPEWDISPEAKDLIRKL 234

                           90
                   ....*....|....
gi 1238280194  105 WEANPEARPTFPGI 118
Cdd:smart00220 235 LVKDPEKRLTAEEA 248

Catalytic (repeat 2) domain of the Protein Tyrosine Kinases, Janus kinases; The Jak subfamily is composed of Jak1, Jak2, Jak3, TYK2, and similar proteins. They are PTKs, catalyzing the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Jaks are cytoplasmic (or nonreceptor) PTKs containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase catalytic domain. Most Jaks are expressed in a wide variety of tissues, except for Jak3, which is expressed only in hematopoietic cells. Jaks are crucial for cytokine receptor signaling. They are activated by autophosphorylation upon cytokine-induced receptor aggregation, and subsequently trigger downstream signaling events such as the phosphorylation of signal transducers and activators of transcription (STATs). Jaks are also involved in regulating the surface expression of some cytokine receptors. The Jak-STAT pathway is involved in many biological processes including hematopoiesis, immunoregulation, host defense, fertility, lactation, growth, and embryogenesis. The Jak 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 1238280194  31 APEHLNDvnAKPTEKSDVYSFAVVLWAIFANKEPYENAI--------CEQ------QLIMCIKSG---NRPDvdditeYC 93
Cdd:cd05038   180 APECLRE--SRFSSASDVWSFGVTLYELFTYGDPSQSPPalflrmigIAQgqmivtRLLELLKSGerlPRPP------SC 251

                          90       100
                  ....*....|....*....|....*....
gi 1238280194  94 PREIISLMKLCWEANPEARPTFPGIEEKF 122
Cdd:cd05038   252 PDEVYDLMKECWEYEPQDRPSFSDLILII 280

Catalytic domain of the Protein Tyrosine Kinase, Fes; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Fes (or Fps) is a cytoplasmic (or nonreceptor) PTK 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 PTK activity. Fes kinase is expressed in myeloid, vascular endothelial, epithelial, and neuronal cells. It plays important roles in cell growth and differentiation, angiogenesis, inflammation and immunity, and cytoskeletal regulation. A recent study implicates Fes kinase as a tumor suppressor in colorectal cancer. The Fes 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 1238280194  15 EVDGTAKKNGGT----LYYMAPEHLNdvNAKPTEKSDVYSFAVVLWAIFA-NKEPYENaICEQQLIMCIKSGNRPDVddi 89
Cdd:cd05084   145 EEDGVYAATGGMkqipVKWTAPEALN--YGRYSSESDVWSFGILLWETFSlGAVPYAN-LSNQQTREAVEQGVRLPC--- 218

                          90       100
                  ....*....|....*....|....*.
gi 1238280194  90 TEYCPREIISLMKLCWEANPEARPTF 115
Cdd:cd05084   219 PENCPDEVYRLMEQCWEYDPRKRPSF 244

Catalytic domain of the Serine/Threonine Kinase, A-Raf (Rapidly Accelerated Fibrosarcoma) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. A-Raf cooperates with C-Raf in regulating ERK transient phosphorylation that is associated with cyclin D expression and cell cycle progression. Mice deficient in A-Raf are born alive but show neurological and intestinal defects. A-Raf demonstrates low kinase activity to MEK, compared with B- and C-Raf, and may also have alternative functions other than in the ERK signaling cascade. It regulates the M2 type pyruvate kinase, a key glycolytic enzyme. It also plays a role in endocytic membrane trafficking. A-Raf is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. It functions in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. The A-Raf subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1238280194  25 GTLYYMAPEHLNDVNAKP-TEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMCIKSGN-RPDVDDITEYCPREIISLMK 102
Cdd:cd14150   160 GSILWMAPEVIRMQDTNPySFQSDVYAYGVVLYELMSGTLPYSNINNRDQIIFMVGRGYlSPDLSKLSSNCPKAMKRLLI 239

                          90
                  ....*....|....*.
gi 1238280194 103 LCWEANPEARPTFPGI 118
Cdd:cd14150   240 DCLKFKREERPLFPQI 255

Catalytic domain of the Protein Tyrosine Kinase, REarranged during Transfection protein; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. RET is a receptor PTK (RTK) containing an extracellular region with four cadherin-like repeats, a calcium-binding site, and a cysteine-rich domain, a transmembrane segment, and an intracellular catalytic domain. It is part of a multisubunit complex that binds glial-derived neurotropic factor (GDNF) family ligands (GFLs) including GDNF, neurturin, artemin, and persephin. GFLs bind RET along with four GPI-anchored coreceptors, bringing two RET molecules together, leading to autophosphorylation, activation, and intracellular signaling. RET is essential for the development of the sympathetic, parasympathetic and enteric nervous systems, and the kidney. RET disruption by germline mutations causes diseases in humans including congenital aganglionosis of the gastrointestinal tract (Hirschsprung's disease) and three related inherited cancers: multiple endocrine neoplasia type 2A (MEN2A), MEN2B, and familial medullary thyroid carcinoma. The RET 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 1238280194  15 EVDGTAKKNGGTL--YYMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFA-NKEPYEnAICEQQLIMCIKSGNRPDVddiTE 91
Cdd:cd05045   179 EEDSYVKRSKGRIpvKWMAIESLFD--HIYTTQSDVWSFGVLLWEIVTlGGNPYP-GIAPERLFNLLKTGYRMER---PE 252

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1238280194  92 YCPREIISLMKLCWEANPEARPTFPGIEEKF 122
Cdd:cd05045   253 NCSEEMYNLMLTCWKQEPDKRPTFADISKEL 283

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 1238280194  27 LYYMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFA-NKEPYENAICEQQLIMCIKSGNRPDVddiTEYCPREIISLMKLCW 105
Cdd:cd05102   238 LKWMAPESIFD--KVYTTQSDVWSFGVLLWEIFSlGASPYPGVQINEEFCQRLKDGTRMRA---PEYATPEIYRIMLSCW 312

                          90
                  ....*....|....*
gi 1238280194 106 EANPEARPTFPGIEE 120
Cdd:cd05102   313 HGDPKERPTFSDLVE 327

Catalytic domain of Ephrin Receptor Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EphRs comprise the largest subfamily of receptor PTKs (RTKs). They can be classified into two classes (EphA and EphB), according to their extracellular sequences, which largely correspond to binding preferences for either GPI-anchored ephrin-A ligands or transmembrane ephrin-B ligands. Vertebrates have ten EphA and six EphB receptors, which display promiscuous ligand interactions within each class. EphRs contain an ephrin binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyr kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. This allows ephrin/EphR dimers to form, leading to the activation of the intracellular tyr kinase domain. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). The main effect of ephrin/EphR interaction is cell-cell repulsion or adhesion. Ephrin/EphR signaling is important in neural development and plasticity, cell morphogenesis and proliferation, cell-fate determination, embryonic development, tissue patterning, and angiogenesis.The EphR 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 1238280194  12 ELREVDGTAKKNGG--TLYYMAPEHLNdvNAKPTEKSDVYSFAVVLWAIFANKE-PYENaICEQQLIMCIKSGNR--PDV 86
Cdd:cd05033   155 RLEDSEATYTTKGGkiPIRWTAPEAIA--YRKFTSASDVWSFGIVMWEVMSYGErPYWD-MSNQDVIKAVEDGYRlpPPM 231

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1238280194  87 DditeyCPREIISLMKLCWEANPEARPTFPGI 118
Cdd:cd05033   232 D-----CPSALYQLMLDCWQKDRNERPTFSQI 258

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 1238280194  27 LYYMAPEHLNdvNAKPTEKSDVYSFAVVLWAIFA-NKEPYENaICEQQLIMCIKSGNRPDVddiTEYCPREIISLMKLCW 105
Cdd:cd05115   171 LKWYAPECIN--FRKFSSRSDVWSYGVTMWEAFSyGQKPYKK-MKGPEVMSFIEQGKRMDC---PAECPPEMYALMSDCW 244

                          90       100
                  ....*....|....*....|...
gi 1238280194 106 EANPEARPTFPGIEEKFRPFYLS 128
Cdd:cd05115   245 IYKWEDRPNFLTVEQRMRTYYYS 267

Catalytic domain of the Protein Tyrosine Kinase, Fibroblast Growth Factor Receptor 1; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Alternative splicing of FGFR1 transcripts produces a variety of isoforms, which are differentially expressed in cells. FGFR1 binds the ligands, FGF1 and FGF2, with high affinity and has also been reported to bind FGF4, FGF6, and FGF9. FGFR1 signaling is critical in the control of cell migration during embryo development. It promotes cell proliferation in fibroblasts. Nuclear FGFR1 plays a role in the regulation of transcription. Mutations, insertions or deletions of FGFR1 have been identified in patients with Kallman's syndrome (KS), an inherited disorder characterized by hypogonadotropic hypogonadism and loss of olfaction. Aberrant FGFR1 expression has been found in some human cancers including 8P11 myeloproliferative syndrome (EMS), breast cancer, and pancreatic adenocarcinoma. FGFR1 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 FGFR1 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 1238280194  12 ELREVDGTAKKNGGTL--YYMAPEHLNDvnAKPTEKSDVYSFAVVLWAIFA-NKEPYENAICEQqLIMCIKSGNRPDVdd 88
Cdd:cd05098   184 DIHHIDYYKKTTNGRLpvKWMAPEALFD--RIYTHQSDVWSFGVLLWEIFTlGGSPYPGVPVEE-LFKLLKEGHRMDK-- 258