Bruton's tyrosine kinase pleckstrin homology (PH) domain; Btk is a member of the Tec family of cytoplasmic protein tyrosine kinases that includes BMX, IL2-inducible T-cell kinase (Itk) and Tec. Btk plays a role in the maturation of B cells. Tec proteins general have an N-terminal PH domain, followed by a Tek homology (TH) domain, a SH3 domain, a SH2 domain and a kinase domain. The Btk PH domain binds phosphatidylinositol 3,4,5-trisphosphate and responds to signalling via phosphatidylinositol 3-kinase. The PH domain is also involved in membrane anchoring which is confirmed by the discovery of a mutation of a critical arginine residue in the BTK PH domain. This results in severe human immunodeficiency known as X-linked agammaglobulinemia (XLA) in humans and a related disorder is mice.PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227   6 LESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERgrRGSKKGSIDVEKITCVETVVPEknPPPERqiprrgee 85
Cdd:cd01238    1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEK--RGKEKGSIDLSKVRCVEEVKDE--AFFER-------- 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227  86 ssemeqisiierfPYPFQVVYDEGPLYVFSPTEELRKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGC 165
Cdd:cd01238   69 -------------KYPFQVVYDDYTLYVFAPSEEDRDEWIAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKSAPGC 135

                 .
gi 565324227 166 Q 166
Cdd:cd01238  136 Q 136

Src Homology 3 domain of Bruton's tyrosine kinase; BTK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions. Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 565324227 217 KKVVALYDYMPMNANDLQLRKGDEYFILEESNLPWWRARDKNGQEGYIPSNYVTE 271
Cdd:cd11906    1 KKVVALYDYTPMNAQDLQLRKGEEYVILEESNLPWWRARDKNGREGYIPSNYVTE 55

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227  346 LAARNCLVNDQGVVKVSDFGLSRYVL-DDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:pfam07714 128 LAARNCLVSENLVVKISDFGLSRDIYdDDYYRKRGGGKLPIKWMAPESLKDGKFTSKSDVWSFGVLLWEIFTLGEQPYPG 207

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 565324227  425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNI 475
Cdd:pfam07714 208 MSNEEVLEFLEDGYRLPQPENCPDELYDLMKQCWAYDPEDRPTFSELVEDL 258

Bruton's tyrosine kinase pleckstrin homology (PH) domain; Btk is a member of the Tec family of cytoplasmic protein tyrosine kinases that includes BMX, IL2-inducible T-cell kinase (Itk) and Tec. Btk plays a role in the maturation of B cells. Tec proteins general have an N-terminal PH domain, followed by a Tek homology (TH) domain, a SH3 domain, a SH2 domain and a kinase domain. The Btk PH domain binds phosphatidylinositol 3,4,5-trisphosphate and responds to signalling via phosphatidylinositol 3-kinase. The PH domain is also involved in membrane anchoring which is confirmed by the discovery of a mutation of a critical arginine residue in the BTK PH domain. This results in severe human immunodeficiency known as X-linked agammaglobulinemia (XLA) in humans and a related disorder is mice.PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227   6 LESIFLKRSQQKKKTSPLNFKKRLFLLTVHKLSYYEYDFERgrRGSKKGSIDVEKITCVETVVPEknPPPERqiprrgee 85
Cdd:cd01238    1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEK--RGKEKGSIDLSKVRCVEEVKDE--AFFER-------- 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227  86 ssemeqisiierfPYPFQVVYDEGPLYVFSPTEELRKRWIHQLKNVIRYNSDLVQKYHPCFWIDGQYLCCSQTAKNAMGC 165
Cdd:cd01238   69 -------------KYPFQVVYDDYTLYVFAPSEEDRDEWIAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKSAPGC 135

                 .
gi 565324227 166 Q 166
Cdd:cd01238  136 Q 136

Src Homology 3 domain of Bruton's tyrosine kinase; BTK is a cytoplasmic (or nonreceptor) tyr kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions. Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 565324227 217 KKVVALYDYMPMNANDLQLRKGDEYFILEESNLPWWRARDKNGQEGYIPSNYVTE 271
Cdd:cd11906    1 KKVVALYDYTPMNAQDLQLRKGEEYVILEESNLPWWRARDKNGREGYIPSNYVTE 55

Bruton's tyrosine kinase Cys-rich motif; Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains (but not all PH domains are followed by BTK motifs). The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 565324227   135 NSDLVQKYHPCFWIDGQYLCCSQTAKNAMGCQILEN 170
Cdd:smart00107   1 NNNLLQKYHPSFWVDGKWLCCQQSEKNAPGCTPYEA 36

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227  281 WYSKHMTRSQAEQLLKQEGKEGGFIVRDS-SKAGKYTVSVFAkstgdpQGVIRHYVVCSTPQSQYYLAAR 349
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPDGTFLVRESeSTPGGYTLSVRD------DGKVKHYKIQSTDNGGYYISGG 64

BTK motif; Zinc-binding motif containing conserved cysteines and a histidine. Always found C-terminal to PH domains. The crystal structure shows this motif packs against the PH domain. The PH+Btk module pair has been called the Tec homology (TH) region.

                          10        20
                  ....*....|....*....|....*..
gi 565324227  141 KYHPCFWIDGQYLCCSQTAKNAMGCQI 167
Cdd:pfam00779   1 KYHPGAFVDGKWLCCKQTDKNAPGCSP 27

cyclin-dependent protein kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227 346 LAARNCLVNDQGVVKVSDFGLSR-YVLD--------DEYTSS---VGSKFPVRW-SPPEVLMYS-KFSSKSDIWAFGVLM 411
Cdd:PTZ00024 145 LSPANIFINSKGICKIADFGLARrYGYPpysdtlskDETMQRreeMTSKVVTLWyRAPELLMGAeKYHFAVDMWSVGCIF 224

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 565324227 412 WEIYS-------------LGKMPYERFTNSETAEHIAQGLRLYRPHLASEK 449
Cdd:PTZ00024 225 AELLTgkplfpgeneidqLGRIFELLGTPNEDNWPQAKKLPLYTEFTPRKP 275

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227 350 NCLVNDQGVVKVSDFGLSRYVldDE----YTSSV-GSkfpVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIysL-GKMPYE 423
Cdd:NF033483 137 NILITKDGRVKVTDFGIARAL--SSttmtQTNSVlGT---VHYLSPEQARGGTVDARSDIYSLGIVLYEM--LtGRPPFD 209

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERF 425
Cdd:cd05059  126 LAARNCLVGEQNVVKVSDFGLARYVLDDEYTSSVGTKFPVKWSPPEVFMYSKFSSKSDVWSFGVLMWEVFSEGKMPYERF 205

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 565324227 426 TNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNIL 476
Cdd:cd05059  206 SNSEVVEHISQGYRLYRPHLAPTEVYTIMYSCWHEKPEERPTFKILLSQLT 256

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227  346 LAARNCLVNDQGVVKVSDFGLSRYVL-DDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:pfam07714 128 LAARNCLVSENLVVKISDFGLSRDIYdDDYYRKRGGGKLPIKWMAPESLKDGKFTSKSDVWSFGVLLWEIFTLGEQPYPG 207

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 565324227  425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNI 475
Cdd:pfam07714 208 MSNEEVLEFLEDGYRLPQPENCPDELYDLMKQCWAYDPEDRPTFSELVEDL 258

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 565324227   346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERF 425
Cdd:smart00221 129 LAARNCLVGENLVVKISDFGLSRDLYDDDYYKVKGGKLPIRWMAPESLKEGKFTSKSDVWSFGVLLWEIFTLGEEPYPGM 208

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*..
gi 565324227   426 TNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILL 472
Cdd:smart00221 209 SNAEVLEYLKKGYRLPKPPNCPPELYKLMLQCWAEDPEDRPTFSELV 255

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERF 425
Cdd:cd05112  126 LAARNCLVGENQVVKVSDFGMTRFVLDDQYTSSTGTKFPVKWSSPEVFSFSRYSSKSDVWSFGVLMWEVFSEGKIPYENR 205

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 565324227 426 TNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILL 472
Cdd:cd05112  206 SNSEVVEDINAGFRLYKPRLASTHVYEIMNHCWKERPEDRPSFSLLL 252

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERF 425
Cdd:cd05034  118 LAARNILVGENNVCKVADFGLARLIEDDEYTAREGAKFPIKWTAPEAALYGRFTIKSDVWSFGILLYEIVTYGRVPYPGM 197

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 565324227 426 TNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLS 473
Cdd:cd05034  198 TNREVLEQVERGYRMPKPPGCPDELYDIMLQCWKKEPEERPTFEYLQS 245

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSK-FPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:cd05041  120 LAARNCLVGENNVLKISDFGMSREEEDGEYTVSDGLKqIPIKWTAPEALNYGRYTSESDVWSFGILLWEIFSLGATPYPG 199

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 565324227 425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTF 468
Cdd:cd05041  200 MSNQQTREQIESGYRMPAPELCPEAVYRLMLQCWAYDPENRPSF 243

Src homology 2 (SH2) domain found in Tec protein, Bruton's tyrosine kinase (Btk); A member of the Tec protein tyrosine kinase Btk is expressed in bone marrow, spleen, all hematopoietic cells except T lymphocytes and plasma cells where it plays a crucial role in B cell maturation and mast cell activation. Btk has been shown to interact with GNAQ, PLCG2, protein kinase D1, B-cell linker, SH3BP5, caveolin 1, ARID3A, and GTF2I. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains and it's lack of presence in Txk is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. Two tyrosine phosphorylation (pY) sites have been identified in Btk: one located in the activation loop of the catalytic domain which regulates the transition between open (active) and closed (inactive) states and the other in its SH3 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 565324227 274 DSIEMYEWYSKHMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKSTGDPQGVIRHYVVCSTPQSQYYLAARN 350
Cdd:cd10397    1 DSLEMYEWYSKNMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKSAGDPQGVIRHYVVCSTPQSQYYLAEKH 77

Catalytic domain of Spleen Tyrosine Kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. The Syk-like subfamily is composed of Syk, ZAP-70, Shark, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing two Src homology 2 (SH2) domains N-terminal to the catalytic tyr kinase domain. They are involved in the signaling downstream of activated receptors (including B-cell, T-cell, and Fc receptors) that contain ITAMs (immunoreceptor tyr activation motifs), leading to processes such as cell proliferation, differentiation, survival, adhesion, migration, and phagocytosis. Syk is important in B-cell receptor signaling, while Zap-70 is primarily expressed in T-cells and NK cells, and is a crucial component in T-cell receptor signaling. Syk also plays a central role in Fc receptor-mediated phagocytosis in the adaptive immune system. Shark is exclusively expressed in ectodermally derived epithelia, and is localized preferentially to the apical surface of the epithelial cells, it may play a role in a signaling pathway for epithelial cell polarity. The Syk-like subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVL--DDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYE 423
Cdd:cd05060  121 LAARNVLLVNRHQAKISDFGMSRALGagSDYYRATTAGRWPLKWYAPECINYGKFSSKSDVWSYGVTLWEAFSYGAKPYG 200

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 565324227 424 RFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTF 468
Cdd:cd05060  201 EMKGPEVIAMLESGERLPRPEECPQEIYSIMLSCWKYRPEDRPTF 245

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSK-FPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:cd05084  121 LAARNCLVTEKNVLKISDFGMSREEEDGVYAATGGMKqIPVKWTAPEALNYGRYSSESDVWSFGILLWETFSLGAVPYAN 200

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 565324227 425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKIL 471
Cdd:cd05084  201 LSNQQTREAVEQGVRLPCPENCPDEVYRLMEQCWEYDPRKRPSFSTV 247

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 565324227 346 LAARNCLVNDQG----VVKVSDFGLSRYVLDDEYTSSVGS-KFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKM 420
Cdd:cd05044  132 LAARNCLVSSKDyrerVVKIGDFGLARDIYKNDYYRKEGEgLLPVRWMAPESLVDGVFTTQSDVWAFGVLMWEILTLGQQ 211

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 565324227 421 PYERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILD 477
Cdd:cd05044  212 PYPARNNLEVLHFVRAGGRLDQPDNCPDDLYELMLRCWSTDPEERPSFARILEQLQN 268

Catalytic domain of the Protein Tyrosine Kinase, Focal Adhesion Kinase; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. FAK is a cytoplasmic (or nonreceptor) PTK that contains an autophosphorylation site and a FERM domain at the N-terminus, a central tyr kinase domain, proline-rich regions, and a C-terminal FAT (focal adhesion targeting) domain. FAK activity is dependent on integrin-mediated cell adhesion, which facilitates N-terminal autophosphorylation. Full activation is achieved by the phosphorylation of its two adjacent A-loop tyrosines. FAK is important in mediating signaling initiated at sites of cell adhesions and at growth factor receptors. Through diverse molecular interactions, FAK functions as a biosensor or integrator to control cell motility. It is a key regulator of cell survival, proliferation, migration and invasion, and thus plays an important role in the development and progression of cancer. Src binds to autophosphorylated FAK forming the FAK-Src dual kinase complex, which is activated in a wide variety of tumor cells and generates signals promoting growth and metastasis. FAK is being developed as a target for cancer therapy. The FAK 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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDE-YTSSVGsKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:cd05056  133 IAARNVLVSSPDCVKLGDFGLSRYMEDESyYKASKG-KLPIKWMAPESINFRRFTSASDVWMFGVCMWEILMLGVKPFQG 211

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 565324227 425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILDVMDEES 483
Cdd:cd05056  212 VKNNDVIGRIENGERLPMPPNCPPTLYSLMTKCWAYDPSKRPRFTELKAQLSDILQEEK 270

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYERF 425
Cdd:cd05085  120 LAARNCLVGENNALKISDFGMSRQEDDGVYSSSGLKQIPIKWTAPEALNYGRYSSESDVWSFGILLWETFSLGVCPYPGM 199

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 565324227 426 TNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTF 468
Cdd:cd05085  200 TNQQAREQVEKGYRMSAPQRCPEDIYKIMQRCWDYNPENRPKF 242

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDD---EYTSSvGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPY 422
Cdd:cd05063  133 LAARNILVNSNLECKVSDFGLSRVLEDDpegTYTTS-GGKIPIRWTAPEAIAYRKFTSASDVWSFGIVMWEVMSFGERPY 211

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 565324227 423 ERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLsNILD 477
Cdd:cd05063  212 WDMSNHEVMKAINDGFRLPAPMDCPSAVYQLMLQCWQQDRARRPRFVDIV-NLLD 265

Catalytic domain of the Protein Tyrosine Kinases, Met and Ron; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Met and Ron are receptor PTKs (RTKs) composed of an alpha-beta heterodimer. The extracellular alpha chain is disulfide linked to the beta chain, which contains an extracellular ligand-binding region with a sema domain, a PSI domain and four IPT repeats, a transmembrane segment, and an intracellular catalytic domain. Binding to their ligands leads to receptor dimerization, autophosphorylation, activation, and intracellular signaling. Met binds to the ligand, hepatocyte growth factor/scatter factor (HGF/SF), and is also called the HGF receptor. HGF/Met signaling plays a role in growth, transformation, cell motility, invasion, metastasis, angiogenesis, wound healing, and tissue regeneration. Aberrant expression of Met through mutations or gene amplification is associated with many human cancers including hereditary papillary renal and gastric carcinomas. The ligand for Ron is macrophage stimulating protein (MSP). Ron signaling is important in regulating cell motility, adhesion, proliferation, and apoptosis. Aberrant Ron expression is implicated in tumorigenesis and metastasis. The Met/Ron 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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTS---SVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPY 422
Cdd:cd05058  124 LAARNCMLDESFTVKVADFGLARDIYDKEYYSvhnHTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPY 203

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 565324227 423 ERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNI 475
Cdd:cd05058  204 PDVDSFDITVYLLQGRRLLQPEYCPDPLYEVMLSCWHPKPEMRPTFSELVSRI 256

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLD-DEYTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:cd05053  159 LAARNVLVTEDNVMKIADFGLARDIHHiDYYRKTTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPG 238

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 565324227 425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNiLDVM 479
Cdd:cd05053  239 IPVEELFKLLKEGHRMEKPQNCTQELYMLMRDCWHEVPSQRPTFKQLVED-LDRI 292

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDEYTSSVG-SKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPYER 424
Cdd:cd05032  145 LAARNCMVAEDLTVKIGDFGMTRDIYETDYYRKGGkGLLPVRWMAPESLKDGVFTTKSDVWSFGVVLWEMATLAEQPYQG 224

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 565324227 425 FTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSNILD 477
Cdd:cd05032  225 LSNEEVLKFVIDGGHLDLPENCPDKLLELMRMCWQYNPKMRPTFLEIVSSLKD 277

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDD---EYTSSvGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMPY 422
Cdd:cd05066  132 LAARNILVNSNLVCKVSDFGLSRVLEDDpeaAYTTR-GGKIPIRWTAPEAIAYRKFTSASDVWSYGIVMWEVMSYGERPY 210

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 565324227 423 ERFTNSETAEHIAQGLRLYRPHLASEKVYTIMYSCWHEKADERPTFKILLSnILDVM 479
Cdd:cd05066  211 WEMSNQDVIKAIEEGYRLPAPMDCPAALHQLMLDCWQKDRNERPKFEQIVS-ILDKL 266

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 565324227 346 LAARNCLVNDQGVVKVSDFGLSRYVLDDE----YTSSVGSKFPVRWSPPEVLMYSKFSSKSDIWAFGVLMWEIYSLGKMP 421
Cdd:cd05065  132 LAARNILVNSNLVCKVSDFGLSRFLEDDTsdptYTSSLGGKIPIRWTAPEAIAYRKFTSASDVWSYGIVMWEVMSYGERP 211