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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYV 80
Cdd:cd14203  28 KPGTMSPEAFLEEAQIMKKLRHDKLVQLYAVVSEEPIYIVTEFMSKGSLLDFLKDGEGKYLKLPQLVDMAAQIASGMAYI 107

                        90       100
                ....*....|....*....|...
gi 472744    81 ERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd14203 108 ERMNYIHRDLRAANILVGDNLVC 130

Catalytic domain of a subset of 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 includes a subset of Src-like PTKs including Src, Fyn, Yrk, and Yes, which are all widely expressed. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells and tumor vasculature, contributing to cancer progression and metastasis. They are also implicated in acute inflammatory responses and osteoclast function. The Src/Fyn-like 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYV 80
Cdd:cd14203  28 KPGTMSPEAFLEEAQIMKKLRHDKLVQLYAVVSEEPIYIVTEFMSKGSLLDFLKDGEGKYLKLPQLVDMAAQIASGMAYI 107

                        90       100
                ....*....|....*....|...
gi 472744    81 ERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd14203 108 ERMNYIHRDLRAANILVGDNLVC 130

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 472744        8 EAFLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYVERMNYV 86
Cdd:smart00221  46 EEFLREARIMRKLDHPNIVKLLGVCTEeEPLMIVMEYMPGGDLLDYLRKNRPKELSLSDLLSFALQIARGMEYLESKNFI 125

                           90
                   ....*....|....*..
gi 472744       87 HRDLRAANILVGDNLVC 103
Cdd:smart00221 126 HRDLAARNCLVGENLVV 142

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 472744     10 FLQEAQVMKKLRHEKLVQLYAVVSEEPI-YIVTEFMDQGSLLEFLKGQYstmlRLP--QLVDFASQIASGMAYVERMNYV 86
Cdd:NF033483  54 FRREAQSAASLSHPNIVSVYDVGEDGGIpYIVMEYVDGRTLKDYIREHG----PLSpeEAVEIMIQILSALEHAHRNGIV 129

                         90
                 ....*....|....
gi 472744     87 HRDLRAANILVGDN 100
Cdd:NF033483 130 HRDIKPQNILITKD 143

Catalytic domain of a subset of 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 includes a subset of Src-like PTKs including Src, Fyn, Yrk, and Yes, which are all widely expressed. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells and tumor vasculature, contributing to cancer progression and metastasis. They are also implicated in acute inflammatory responses and osteoclast function. The Src/Fyn-like 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYV 80
Cdd:cd14203  28 KPGTMSPEAFLEEAQIMKKLRHDKLVQLYAVVSEEPIYIVTEFMSKGSLLDFLKDGEGKYLKLPQLVDMAAQIASGMAYI 107

                        90       100
                ....*....|....*....|...
gi 472744    81 ERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd14203 108 ERMNYIHRDLRAANILVGDNLVC 130

Catalytic domain of Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, and Yes. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, and Lyn show a limited expression pattern. The Src-like 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVS-EEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAY 79
Cdd:cd05034  28 KPGTMSPEAFLQEAQIMKKLRHDKLVQLYAVCSdEEPIYIVTELMSKGSLLDYLRTGEGRALRLPQLIDMAAQIASGMAY 107

                        90       100
                ....*....|....*....|....
gi 472744    80 VERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd05034 108 LESRNYIHRDLAARNILVGENNVC 131

Catalytic domain of the Protein Tyrosine Kinase, Yes; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Yes 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 (PI3K).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYV 80
Cdd:cd05069  45 KPGTMMPEAFLQEAQIMKKLRHDKLVPLYAVVSEEPIYIVTEFMGKGSLLDFLKEGDGKYLKLPQLVDMAAQIADGMAYI 124

                        90       100
                ....*....|....*....|...
gi 472744    81 ERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd05069 125 ERMNYIHRDLRAANILVGDNLVC 147

Catalytic domain of the Protein Tyrosine Kinase, Lyn; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Lyn 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVS-EEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAY 79
Cdd:cd05072  40 KPGTMSVQAFLEEANLMKTLQHDKLVRLYAVVTkEEPIYIITEYMAKGSLLDFLKSDEGGKVLLPKLIDFSAQIAEGMAY 119

                        90       100
                ....*....|....*....|....
gi 472744    80 VERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd05072 120 IERKNYIHRDLRAANVLVSESLMC 143

Catalytic domain of the Protein Tyrosine Kinase, Hematopoietic cell kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Hck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Hck is present in myeloid and lymphoid cells that play a role in the development of cancer. It may be important in the oncogenic signaling of the protein Tel-Abl, which induces a chronic myelogenous leukemia (CML)-like disease. Hck also acts as a negative regulator of G-CSF-induced proliferation of granulocytic precursors, suggesting a possible role in the development of acute myeloid leukemia (AML). In addition, Hck is essential in regulating the degranulation of polymorphonuclear leukocytes. Genetic polymorphisms affect the expression level of Hck, which affects PMN mediator release and influences the development of chronic obstructive pulmonary disease (COPD). Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The Hck 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYV 80
Cdd:cd05073  44 KPGSMSVEAFLAEANVMKTLQHDKLVKLHAVVTKEPIYIITEFMAKGSLLDFLKSDEGSKQPLPKLIDFSAQIAEGMAFI 123

                        90       100
                ....*....|....*....|...
gi 472744    81 ERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd05073 124 EQRNYIHRDLRAANILVSASLVC 146

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 472744        8 EAFLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYVERMNYV 86
Cdd:smart00221  46 EEFLREARIMRKLDHPNIVKLLGVCTEeEPLMIVMEYMPGGDLLDYLRKNRPKELSLSDLLSFALQIARGMEYLESKNFI 125

                           90
                   ....*....|....*..
gi 472744       87 HRDLRAANILVGDNLVC 103
Cdd:smart00221 126 HRDLAARNCLVGENLVV 142

Catalytic domain of the Protein Tyrosine Kinases, Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (Srm) and Breast tumor kinase (Brk); PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Srm and Brk (also called protein tyrosine kinase 6) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Brk has been found to be overexpressed in a majority of breast tumors. Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). Srm and Brk however, lack the N-terminal myristylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. The Srm/Brk 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 472744    10 FLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYVERMNYVHR 88
Cdd:cd05148  49 FQKEVQALKRLRHKHLISLFAVCSVgEPVYIITELMEKGSLLAFLRSPEGQVLPVASLIDMACQVAEGMAYLEEQNSIHR 128

                        90
                ....*....|....*
gi 472744    89 DLRAANILVGDNLVC 103
Cdd:cd05148 129 DLAARNILVGEDLVC 143

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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEE-PIYIVTEFMDQGSLLEFLKgQYSTMLRLPQLVDFASQIASGMAY 79
Cdd:cd05059  37 KEGSMSEDDFIEEAKVMMKLSHPKLVQLYGVCTKQrPIFIVTEYMANGCLLNYLR-ERRGKFQTEQLLEMCKDVCEAMEY 115

                        90       100
                ....*....|....*....|...
gi 472744    80 VERMNYVHRDLRAANILVGDNLV 102
Cdd:cd05059 116 LESNGFIHRDLAARNCLVGEQNV 138

Catalytic domain of the Protein Tyrosine Kinase, Abelson kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Abl (or c-Abl) is a ubiquitously-expressed cytoplasmic (or nonreceptor) PTK that contains SH3, SH2, and tyr kinase domains in its N-terminal region, as well as nuclear localization motifs, a putative DNA-binding domain, and F- and G-actin binding domains in its C-terminal tail. It also contains a short autoinhibitory cap region in its N-terminus. Abl function depends on its subcellular localization. In the cytoplasm, Abl plays a role in cell proliferation and survival. In response to DNA damage or oxidative stress, Abl is transported to the nucleus where it induces apoptosis. In chronic myelogenous leukemia (CML) patients, an aberrant translocation results in the replacement of the first exon of Abl with the BCR (breakpoint cluster region) gene. The resulting BCR-Abl fusion protein is constitutively active and associates into tetramers, resulting in a hyperactive kinase sending a continuous signal. This leads to uncontrolled proliferation, morphological transformation and anti-apoptotic effects. BCR-Abl is the target of selective inhibitors, such as imatinib (Gleevec), used in the treatment of CML. Abl2, also known as ARG (Abelson-related gene), is thought to play a cooperative role with Abl in the proper development of the nervous system. The Tel-ARG fusion protein, resulting from reciprocal translocation between chromosomes 1 and 12, is associated with acute myeloid leukemia (AML). The TEL gene is a frequent fusion partner of other tyr kinase oncogenes, including Tel/Abl, Tel/PDGFRbeta, and Tel/Jak2, found in patients with leukemia and myeloproliferative disorders. The Abl 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEE-PIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAY 79
Cdd:cd05052  40 KEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREpPFYIITEFMPYGNLLDYLRECNREELNAVVLLYMATQIASAMEY 119

                        90       100
                ....*....|....*....|.
gi 472744    80 VERMNYVHRDLRAANILVGDN 100
Cdd:cd05052 120 LEKKNFIHRDLAARNCLVGEN 140

Catalytic domain of the Protein Tyrosine Kinase, Interleukin-2-inducible T-cell Kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Itk, also known as Tsk or Emt, is a member of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, Itk contains the Tec homology (TH) domain containing one proline-rich region and a zinc-binding region. Itk is expressed in T-cells and mast cells, and is important in their development and differentiation. Of the three Tec kinases expressed in T-cells, Itk plays the predominant role in T-cell receptor (TCR) signaling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization. It also plays a role in the downstream signaling of the T-cell costimulatory receptor CD28, the T-cell surface receptor CD2, and the chemokine receptor CXCR4. In addition, Itk is crucial for the development of T-helper(Th)2 effector responses. The Itk 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 472744     1 KPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEE-PIYIVTEFMDQGSLLEFLKGQYStMLRLPQLVDFASQIASGMAY 79
Cdd:cd05112  37 REGAMSEEDFIEEAEVMMKLSHPKLVQLYGVCLEQaPICLVFEFMEHGCLSDYLRTQRG-LFSAETLLGMCLDVCEGMAY 115

                        90       100
                ....*....|....*....|...
gi 472744    80 VERMNYVHRDLRAANILVGDNLV 102
Cdd:cd05112 116 LEEASVIHRDLAARNCLVGENQV 138

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 472744    10 FLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLK---GQYSTMlrlpQLVDFASQIASGMAYVERMNY 85
Cdd:cd05033  52 FLTEASIMGQFDHPNVIRLEGVVTKsRPVMIVTEYMENGSLDKFLRendGKFTVT----QLVGMLRGIASGMKYLSEMNY 127

                        90
                ....*....|....*...
gi 472744    86 VHRDLRAANILVGDNLVC 103
Cdd:cd05033 128 VHRDLAARNILVNSDLVC 145

Catalytic domain of the Protein Tyrosine Kinases, Tyrosine kinase expressed in hepatocellular carcinoma and Resting lymphocyte kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Tec and Rlk (also named Txk) are members of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. Instead of PH, Rlk contains an N-terminal cysteine-rich region. In addition to PH, Tec also contains the Tec homology (TH) domain with proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells. Tec is more widely-expressed than other Tec-like subfamily kinases. It is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils. Rlk is expressed in T-cells and mast cell lines. Tec and Rlk are both key components of T-cell receptor (TCR) signaling. They are important in TCR-stimulated proliferation, IL-2 production and phopholipase C-gamma1 activation. The Tec/Rlk 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 472744     3 GTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEE-PIYIVTEFMDQGSLLEFLKGQYStMLRLPQLVDFASQIASGMAYVE 81
Cdd:cd05114  39 GAMSEEDFIEEAKVMMKLTHPKLVQLYGVCTQQkPIYIVTEFMENGCLLNYLRQRRG-KLSRDMLLSMCQDVCEGMEYLE 117

                        90
                ....*....|....*...
gi 472744    82 RMNYVHRDLRAANILVGD 99
Cdd:cd05114 118 RNNFIHRDLAARNCLVND 135

Catalytic domain of the Protein Tyrosine Kinases, Class EphB Ephrin Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Class EphB receptors bind to transmembrane ephrin-B ligands. There are six vertebrate EphB receptors (EphB1-6), which display promiscuous interactions with three ephrin-B ligands. One exception is EphB2, which also interacts with ephrin A5. EphB receptors play important roles in synapse formation and plasticity, spine morphogenesis, axon guidance, and angiogenesis. In the intestinal epithelium, EphBs are Wnt signaling target genes that control cell compartmentalization. They function as suppressors of colon cancer progression. EphRs comprise the largest subfamily of receptor PTKs (RTKs). They 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. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). Ephrin/EphR interaction mainly results in cell-cell repulsion or adhesion. The EphB 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 472744    10 FLQEAQVMKKLRHEKLVQLYAVVSEE-PIYIVTEFMDQGSLLEFLK---GQYSTMlrlpQLVDFASQIASGMAYVERMNY 85
Cdd:cd05065  52 FLSEASIMGQFDHPNIIHLEGVVTKSrPVMIITEFMENGALDSFLRqndGQFTVI----QLVGMLRGIAAGMKYLSEMNY 127

                        90
                ....*....|....*...
gi 472744    86 VHRDLRAANILVGDNLVC 103
Cdd:cd05065 128 VHRDLAARNILVNSNLVC 145

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 472744     4 TMSPE---AFLQEAQVMKKLRHEKLVQLYAV-VSEEPIYIVTEFMDQGSLLEFLKGQySTMLRLPQLVDFASQIASGMAY 79
Cdd:cd05041  31 TLPPDlkrKFLQEARILKQYDHPNIVKLIGVcVQKQPIMIVMELVPGGSLLTFLRKK-GARLTVKQLLQMCLDAAAGMEY 109

                        90       100
                ....*....|....*....|.
gi 472744    80 VERMNYVHRDLRAANILVGDN 100
Cdd:cd05041 110 LESKNCIHRDLAARNCLVGEN 130

Catalytic domain of the Protein Tyrosine Kinases, Class EphA Ephrin Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of most class EphA receptors including EphA3, EphA4, EphA5, and EphA7, but excluding EphA1, EphA2 and EphA10. Class EphA receptors bind GPI-anchored ephrin-A ligands. There are ten vertebrate EphA receptors (EphA1-10), which display promiscuous interactions with six ephrin-A ligands. One exception is EphA4, which also binds ephrins-B2/B3. EphA receptors and ephrin-A ligands are expressed in multiple areas of the developing brain, especially in the retina and tectum. They are part of a system controlling retinotectal mapping. EphRs comprise the largest subfamily of receptor PTKs (RTKs). 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. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). Ephrin/EphR interaction mainly results in cell-cell repulsion or adhesion, making it important in neural development and plasticity, cell morphogenesis, cell-fate determination, embryonic development, tissue patterning, and angiogenesis. The EphA 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 472744    10 FLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLK---GQYSTMlrlpQLVDFASQIASGMAYVERMNY 85
Cdd:cd05066  52 FLSEASIMGQFDHPNIIHLEGVVTRsKPVMIVTEYMENGSLDAFLRkhdGQFTVI----QLVGMLRGIASGMKYLSDMGY 127

                        90
                ....*....|....*...
gi 472744    86 VHRDLRAANILVGDNLVC 103
Cdd:cd05066 128 VHRDLAARNILVNSNLVC 145

Catalytic domain of the Protein Tyrosine Kinase, Ephrin Receptor A2; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The EphA2 receptor is overexpressed in tumor cells and tumor blood vessels in a variety of cancers including breast, prostate, lung, and colon. As a result, it is an attractive target for drug design since its inhibition could affect several aspects of tumor progression. EphRs comprise the largest subfamily of receptor PTKs (RTKs). Class EphA receptors bind GPI-anchored ephrin-A ligands. There are ten vertebrate EphA receptors (EphA1-10), which display promiscuous interactions with six ephrin-A ligands. 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. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling). Ephrin/EphR interaction mainly results in cell-cell repulsion or adhesion, making it important in neural development and plasticity, cell morphogenesis, cell-fate determination, embryonic development, tissue patterning, and angiogenesis. The EphA2 subfamily 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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 472744     1 KPGTMSPEA--FLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLK---GQYSTMlrlpQLVDFASQIA 74
Cdd:cd05063  42 KPGYTEKQRqdFLSEASIMGQFSHHNIIRLEGVVTKfKPAMIITEYMENGALDKYLRdhdGEFSSY----QLVGMLRGIA 117

                        90       100
                ....*....|....*....|....*....
gi 472744    75 SGMAYVERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd05063 118 AGMKYLSDMNYVHRDLAARNILVNSNLEC 146

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 472744     8 EAFLQEAQVMKKLRHEKLVQLYAV-VSEEPIYIVTEFMDQGSLLEFL----------KGQYSTMLRLPQLVDFASQIASG 76
Cdd:cd05051  64 EDFLKEVKIMSQLKDPNIVRLLGVcTRDEPLCMIVEYMENGDLNQFLqkheaetqgaSATNSKTLSYGTLLYMATQIASG 143

                        90       100
                ....*....|....*....|....
gi 472744    77 MAYVERMNYVHRDLRAANILVGDN 100
Cdd:cd05051 144 MKYLESLNFVHRDLATRNCLVGPN 167

Catalytic domain of the Protein Tyrosine Kinase, Fer; Protein Tyrosine Kinase (PTK) family; Fer kinase; catalytic (c) domain. 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. Fer kinase is a member of the Fes subfamily of proteins which 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. Fer kinase is expressed in a wide variety of tissues, and is found to reside in both the cytoplasm and the nucleus. It plays important roles in neuronal polarization and neurite development, cytoskeletal reorganization, cell migration, growth factor signaling, and the regulation of cell-cell interactions mediated by adherens junctions and focal adhesions. Fer kinase also regulates cell cycle progression in malignant cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 472744    10 FLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFLKGQYSTmLRLPQLVDFASQIASGMAYVERMNYVHR 88
Cdd:cd05085  40 FLSEARILKQYDHPNIVKLIGVCTQrQPIYIVMELVPGGDFLSFLRKKKDE-LKTKQLVKFSLDAAAGMAYLESKNCIHR 118

                        90
                ....*....|..
gi 472744    89 DLRAANILVGDN 100
Cdd:cd05085 119 DLAARNCLVGEN 130

Catalytic domain of the Protein Tyrosine Kinase, Tropomyosin Related Kinase A; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. TrkA is a receptor PTK (RTK) containing an extracellular region with arrays of leucine-rich motifs flanked by two cysteine-rich clusters followed by two immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. Binding of TrkA to its ligand, nerve growth factor (NGF), results in receptor oligomerization and activation of the catalytic domain. TrkA is expressed mainly in neural-crest-derived sensory and sympathetic neurons of the peripheral nervous system, and in basal forebrain cholinergic neurons of the central nervous system. It is critical for neuronal growth, differentiation and survival. Alternative TrkA splicing has been implicated as a pivotal regulator of neuroblastoma (NB) behavior. Normal TrkA expression is associated with better NB prognosis, while the hypoxia-regulated TrkAIII splice variant promotes NB pathogenesis and progression. Aberrant TrkA expression has also been demonstrated in non-neural tumors including prostate, breast, lung, and pancreatic cancers. The TrkA 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 472744    10 FLQEAQVMKKLRHEKLVQLYAVVSE-EPIYIVTEFMDQGSLLEFL-------------KGQYSTMLRLPQLVDFASQIAS 75
Cdd:cd05092  54 FQREAELLTVLQHQHIVRFYGVCTEgEPLIMVFEYMRHGDLNRFLrshgpdakildggEGQAPGQLTLGQMLQIASQIAS 133

                        90       100
                ....*....|....*....|....*..
gi 472744    76 GMAYVERMNYVHRDLRAANILVGDNLV 102
Cdd:cd05092 134 GMVYLASLHFVHRDLATRNCLVGQGLV 160

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 472744     9 AFLQEAQVMKKLRHEKLVQLYAVVS-EEPIYIVTEFMDQGSLLEFLKGQYSTMLRLP--------QLVDFASQIASGMAY 79
Cdd:cd05032  55 EFLNEASVMKEFNCHHVVRLLGVVStGQPTLVVMELMAKGDLKSYLRSRRPEAENNPglgpptlqKFIQMAAEIADGMAY 134

                        90       100
                ....*....|....*....|....
gi 472744    80 VERMNYVHRDLRAANILVGDNLVC 103
Cdd:cd05032 135 LAAKKFVHRDLAARNCMVAEDLTV 158

Catalytic domain of Epidermal Growth Factor Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. EGFR (HER, ErbB) subfamily members include EGFR (HER1, ErbB1), HER2 (ErbB2), HER3 (ErbB3), HER4 (ErbB4), and similar proteins. They are receptor PTKs (RTKs) containing an extracellular EGF-related ligand-binding region, a transmembrane helix, and a cytoplasmic region with a tyr kinase domain and a regulatory C-terminal tail. Unlike other PTKs, phosphorylation of the activation loop of EGFR proteins is not critical to their activation. Instead, they are activated by ligand-induced dimerization, resulting in the phosphorylation of tyr residues in the C-terminal tail, which serve as binding sites for downstream signaling molecules. Collectively, they can recognize a variety of ligands including EGF, TGFalpha, and neuregulins, among others. All four subfamily members can form homo- or heterodimers. HER3 contains an impaired kinase domain and depends on its heterodimerization partner for activation. EGFR subfamily members are involved in signaling pathways leading to a broad range of cellular responses including cell proliferation, differentiation, migration, growth inhibition, and apoptosis. Gain of function alterations, through their overexpression, deletions, or point mutations in their kinase domains, have been implicated in various cancers. These receptors are targets of many small molecule inhibitors and monoclonal antibodies used in cancer therapy. The EGFR 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 472744     6 SPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEFMDQGSLLEFLKgQYSTMLRLPQLVDFASQIASGMAYVERMNY 85
Cdd:cd05057  52 ANEEILDEAYVMASVDHPHLVRLLGICLSSQVQLITQLMPLGCLLDYVR-NHRDNIGSQLLLNWCVQIAKGMSYLEEKRL 130

                        90
                ....*....|..
gi 472744    86 VHRDLRAANILV 97
Cdd:cd05057 131 VHRDLAARNVLV 142

Serine/threonine protein kinase [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 472744     8 EAFLQEAQVMKKLRHEKLVQLYAVVSEEPI-YIVTEFMDQGSLLEFLKGQysTMLRLPQLVDFASQIASGMAYVERMNYV 86
Cdd:COG0515  52 ERFRREARALARLNHPNIVRVYDVGEEDGRpYLVMEYVEGESLADLLRRR--GPLPPAEALRILAQLAEALAAAHAAGIV 129

                        90
                ....*....|....
gi 472744    87 HRDLRAANILVGDN 100
Cdd:COG0515 130 HRDIKPANILLTPD 143

Catalytic domain of Discoidin Domain Receptor-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. DDR-like proteins are members of the DDR subfamily, which 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-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 472744    10 FLQEAQVMKKLRHEKLVQLYAV-VSEEPIYIVTEFMDQGSLLEFL-----KGQYSTMLRLP-----QLVDFASQIASGMA 78
Cdd:cd05097  64 FLKEIKIMSRLKNPNIIRLLGVcVSDDPLCMITEYMENGDLNQFLsqreiESTFTHANNIPsvsiaNLLYMAVQIASGMK 143

                        90       100
                ....*....|....*....|...
gi 472744    79 YVERMNYVHRDLRAANILVGDNL 101
Cdd:cd05097 144 YLASLNFVHRDLATRNCLVGNHY 166

Catalytic domain of the Protein Tyrosine Kinase, Discoidin Domain Receptor 2; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. DDR2 is a receptor PTK (RTK) 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 DDR2 results in a slow but sustained receptor activation. DDR2 binds mostly to fibrillar collagens as well as collagen X. DDR2 is widely expressed in many tissues with the highest levels found in skeletal muscle, skin, kidney and lung. It is important in cell proliferation and development. Mice, with a deletion of DDR2, suffer from dwarfism and delayed healing of epidermal wounds. DDR2 also contributes to collagen (type I) regulation by inhibiting fibrillogenesis and altering the morphology of collagen fibers. It is also expressed in immature dendritic cells (DCs), where it plays a role in DC activation and function. The DDR2 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 (PI3K).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 472744    10 FLQEAQVMKKLRHEKLVQLYAV-VSEEPIYIVTEFMDQGSLLEFLKGQY----------STMLRLPQLVDFASQIASGMA 78
Cdd:cd05095  66 FLKEIKIMSRLKDPNIIRLLAVcITDDPLCMITEYMENGDLNQFLSRQQpegqlalpsnALTVSYSDLRFMAAQIASGMK 145

                        90       100
                ....*....|....*....|..
gi 472744    79 YVERMNYVHRDLRAANILVGDN 100
Cdd:cd05095 146 YLSSLNFVHRDLATRNCLVGKN 167

Catalytic domain of the Protein Tyrosine Kinases, Platelet Derived Growth Factor Receptors; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The PDGFR subfamily consists of PDGFR alpha, PDGFR beta, KIT, CSF-1R, the mammalian FLT3, and similar proteins. They are receptor PTKs (RTKs) containing an extracellular ligand-binding region with five immunoglobulin-like domains, a transmembrane segment, and an intracellular catalytic domain. PDGFR kinase domains are autoinhibited by their juxtamembrane regions containing tyr residues. The binding to their ligands leads to receptor dimerization, trans phosphorylation and activation, and intracellular signaling. PDGFR subfamily receptors are important in the development of a variety of cells. PDGFRs are expressed in a many cells including fibroblasts, neurons, endometrial cells, mammary epithelial cells, and vascular smooth muscle cells. PDGFR signaling is critical in normal embryonic development, angiogenesis, and wound healing. Kit is important in the development of melanocytes, germ cells, mast cells, hematopoietic stem cells, the interstitial cells of Cajal, and the pacemaker cells of the GI tract. CSF-1R signaling is critical in the regulation of macrophages and osteoclasts. Mammalian FLT3 plays an important role in the survival, proliferation, and differentiation of stem cells. The PDGFR 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 472744     8 EAFLQEAQVMKKL-RHEKLVQLYAVVSEE-PIYIVTEFMDQGSLLEFLKGQYSTMLRLPQLVDFASQIASGMAYVERMNY 85
Cdd:cd05055  83 EALMSELKIMSHLgNHENIVNLLGACTIGgPILVITEYCCYGDLLNFLRRKRESFLTLEDLLSFSYQVAKGMAFLASKNC 162

                        90
                ....*....|..
gi 472744    86 VHRDLRAANILV 97
Cdd:cd05055 163 IHRDLAARNVLL 174