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 1958677438 363 INPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 442
Cdd:cd05114     1 INPSELTFMKELGSGLFGVVRLGKWRAQYKVAIKAIREGAMSEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958677438 443 MERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05114    81 MENGCLLNYLRQRRGKLSRDMLLSMCQDVCEGMEYLERNNFIHRDL 126

Src homology 2 (SH2) domain found in Tec protein, IL2-inducible T-cell kinase (Itk); A member of the Tec protein tyrosine kinase Itk is expressed thymus, spleen, lymph node, T lymphocytes, NK and mast cells. It plays a role in T-cell proliferation and differentiation, analogous to Tec family kinases Txk. Itk has been shown to interact with Fyn, Wiskott-Aldrich syndrome protein, KHDRBS1, PLCG1, Lymphocyte cytosolic protein 2, Linker of activated T cells, Karyopherin alpha 2, Grb2, and Peptidylprolyl isomerase A. 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. 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. 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 238 NNLDQYEWYCRNTNRSKAEQLLRTEDKEGGFMVRDSSQPGLYTVSLYTKFGGEGSSGFRHYHIKETATSPKKYYLAEKHA 317
Cdd:cd10396     1 NNLDQYEWYNKNINRSKAEKLLRDEGKEGGFMVRDSSQPGLYTVSLYTKAGGEGNPCIRHYHIKETNDSPKKYYLAEKHV 80

                          90       100
                  ....*....|....*....|....*...
gi 1958677438 318 FGSIPEIIEYHKHNAAGLVTRLRYPVST 345
Cdd:cd10396    81 FNSIPELIEYHKHNAAGLVTRLRYPVSS 108

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 1958677438 363 INPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 442
Cdd:cd05114     1 INPSELTFMKELGSGLFGVVRLGKWRAQYKVAIKAIREGAMSEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958677438 443 MERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05114    81 MENGCLLNYLRQRRGKLSRDMLLSMCQDVCEGMEYLERNNFIHRDL 126

Src homology 2 (SH2) domain found in Tec protein, IL2-inducible T-cell kinase (Itk); A member of the Tec protein tyrosine kinase Itk is expressed thymus, spleen, lymph node, T lymphocytes, NK and mast cells. It plays a role in T-cell proliferation and differentiation, analogous to Tec family kinases Txk. Itk has been shown to interact with Fyn, Wiskott-Aldrich syndrome protein, KHDRBS1, PLCG1, Lymphocyte cytosolic protein 2, Linker of activated T cells, Karyopherin alpha 2, Grb2, and Peptidylprolyl isomerase A. 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. 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. 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 238 NNLDQYEWYCRNTNRSKAEQLLRTEDKEGGFMVRDSSQPGLYTVSLYTKFGGEGSSGFRHYHIKETATSPKKYYLAEKHA 317
Cdd:cd10396     1 NNLDQYEWYNKNINRSKAEKLLRDEGKEGGFMVRDSSQPGLYTVSLYTKAGGEGNPCIRHYHIKETNDSPKKYYLAEKHV 80

                          90       100
                  ....*....|....*....|....*...
gi 1958677438 318 FGSIPEIIEYHKHNAAGLVTRLRYPVST 345
Cdd:cd10396    81 FNSIPELIEYHKHNAAGLVTRLRYPVSS 108

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438  368 LTFMRELGSGLFGVVRLGKWRA-----QYKVAIKAIREGAMCE--EDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVT 440
Cdd:smart00219   1 LTLGKKLGEGAFGEVYKGKLKGkggkkKVEVAVKTLKEDASEQqiEEFLREARIMRKLDHPNVVKLLGVCTEEEPLYIVM 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1958677438  441 EFMERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:smart00219  81 EYMEGGDLLSYLRKNRPKLSLSDLLSFALQIARGMEYLESKNFIHRDL 128

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 245 WYCRNTNRSKAEQLLRTEDKEGGFMVRDS-SQPGLYTVSLYTKfggegsSGFRHYHIKETATSpkKYYLAEKHAFGSIPE 323
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPDGTFLVRESeSTPGGYTLSVRDD------GKVKHYKIQSTDNG--GYYISGGVKFSSLAE 72

                  ....*
gi 1958677438 324 IIEYH 328
Cdd:pfam00017  73 LVEHY 77

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1958677438  182 VVAMYDFQATEAHDLRLERGQEYIILEKNDTHWWRARDKYGSEGYIPSNYVT 233
Cdd:smart00326   5 VRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRGKEGLFPSNYVE 56

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 1958677438  113 NNNIMIKYHPKFWADGSYQCCRQTEKLAPGCEKYN 147
Cdd:smart00107   1 NNNLLQKYHPSFWVDGKWLCCQQSEKNAPGCTPYE 35

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438   5 TILEEILIKRSQQKKKtsplNYKERLFVLTKSVLTYYEGRAEKKY--RKGFIDISKIKCVEIVKNDDgiipCQNKFPFQV 82
Cdd:pfam00169   1 VVKEGWLLKKGGGKKK----SWKKRYFVLFDGSLLYYKDDKSGKSkePKGSISLSGCEVVEVVASDS----PKRKFCFEL 72

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958677438  83 VHD----ANTLYIFAPSPQSRDRWVKKLKEEIK 111
Cdd:pfam00169  73 RTGertgKRTYLLQAESEEERKDWIKAIQSAIR 105

Stk1 family PASTA domain-containing Ser/Thr kinase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 393 VAIKAIREgAMCE-EDFIE----EAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEFMErGCLLNFLRQRQGHFSRDVLLSM 467
Cdd:NF033483   35 VAVKVLRP-DLARdPEFVArfrrEAQSAASLSHPNIVSVYDVGEDGGIPYIVMEYVD-GRTLKDYIREHGPLSPEEAVEI 112

                          90       100
                  ....*....|....*....|.
gi 1958677438 468 CQDVCEGMEYLERNSFIHRDL 488
Cdd:NF033483  113 MIQILSALEHAHRNGIVHRDI 133

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 1958677438 363 INPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 442
Cdd:cd05114     1 INPSELTFMKELGSGLFGVVRLGKWRAQYKVAIKAIREGAMSEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958677438 443 MERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05114    81 MENGCLLNYLRQRRGKLSRDMLLSMCQDVCEGMEYLERNNFIHRDL 126

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 1958677438   7 LEEILIKRSQQKKKTSPLNYKERLFVLTKSVLTYYEGRAEKK-YRKGFIDISKIKCVEIVKNDDGiipCQNKFPFQVVHD 85
Cdd:cd01238     1 LEGLLVKRSQGKKRFGPVNYKERWFVLTKSSLSYYEGDGEKRgKEKGSIDLSKVRCVEEVKDEAF---FERKYPFQVVYD 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1958677438  86 ANTLYIFAPSPQSRDRWVKKLKEEIKNNNNIMIKYHPKFWADGSYQCCRQTEKLAPGCEKYNL 148
Cdd:cd01238    78 DYTLYVFAPSEEDRDEWIAALRKVCRNNSNLHDKYHPGFWTGGKWSCCGQTSKSAPGCQPAFD 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 1958677438 363 INPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEF 442
Cdd:cd05112     1 IDPSELTFVQEIGSGQFGLVHLGYWLNKDKVAIKTIREGAMSEEDFIEEAEVMMKLSHPKLVQLYGVCLEQAPICLVFEF 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1958677438 443 MERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05112    81 MEHGCLSDYLRTQRGLFSAETLLGMCLDVCEGMAYLEEASVIHRDL 126

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 1958677438 368 LTFMRELGSGLFGVVRLGKWRAQ-----YKVAIKAIREGAMCE--EDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVT 440
Cdd:pfam07714   1 LTLGEKLGEGAFGEVYKGTLKGEgentkIKVAVKTLKEGADEEerEDFLEEASIMKKLDHPNIVKLLGVCTQGEPLYIVT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1958677438 441 EFMERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:pfam07714  81 EYMPGGDLLDFLRKHKRKLTLKDLLSMALQIAKGMEYLESKNFVHRDL 128

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 238 NNLDQYEWYCRNTNRSKAEQLLRTEDKEGGFMVRDSSQPGLYTVSLYTKFGGEGSSGFRHYHIKETATSpkKYYLAEKHA 317
Cdd:cd10397     1 DSLEMYEWYSKNMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKSAGDPQGVIRHYVVCSTPQS--QYYLAEKHL 78

                          90       100
                  ....*....|....*....|....*...
gi 1958677438 318 FGSIPEIIEYHKHNAAGLVTRLRYPVST 345
Cdd:cd10397    79 FSTIPELINYHQHNAAGLISRLKYPVSS 106

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 1958677438  368 LTFMRELGSGLFGVVRLGKWR-----AQYKVAIKAIREGAMCE--EDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVT 440
Cdd:smart00221   1 LTLGKKLGEGAFGEVYKGTLKgkgdgKEVEVAVKTLKEDASEQqiEEFLREARIMRKLDHPNIVKLLGVCTEEEPLMIVM 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 1958677438  441 EFMERGCLLNFLRQRQGHF-SRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:smart00221  81 EYMPGGDLLDYLRKNRPKElSLSDLLSFALQIARGMEYLESKNFIHRDL 129

Catalytic domain of Fyn-related kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Frk and Srk are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Frk, also known as Rak, is specifically expressed in liver, lung, kidney, intestine, mammary glands, and the islets of Langerhans. Rodent homologs were previously referred to as GTK (gastrointestinal tyr kinase), BSK (beta-cell Src-like kinase), or IYK (intestinal tyr kinase). Studies in mice reveal that Frk is not essential for viability. It plays a role in the signaling that leads to cytokine-induced beta-cell death in Type I diabetes. It also regulates beta-cell number during embryogenesis and early in life. 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 Frk-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 1958677438 359 DKWEINPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYI 438
Cdd:cd05068     1 DQWEIDRKSLKLLRKLGSGQFGEVWEGLWNNTTPVAVKTLKPGTMDPEDFLREAQIMKKLRHPKLIQLYAVCTLEEPIYI 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958677438 439 VTEFMERGCLLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05068    81 ITELMKHGSLLEYLQGKGRSLQLPQLIDMAAQVASGMAYLESQNYIHRDL 130

Catalytic domain of C-terminal Src kinase-like Protein Tyrosine Kinases; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. This subfamily is composed of Csk, Chk, and similar proteins. They are cytoplasmic (or nonreceptor) PTKs containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, Csk and Chk are translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. Csk catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. Chk inhibit Src kinases using a noncatalytic mechanism by simply binding to them. As negative regulators of Src kinases, Csk and Chk play important roles in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. The Csk-like subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as protein serine/threonine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 361 WEINPSELTFMRELGSGLFGVVRLGKWRAQyKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVT 440
Cdd:cd05039     1 WAINKKDLKLGELIGKGEFGDVMLGDYRGQ-KVAVKCLKDDSTAAQAFLAEASVMTTLRHPNLVQLLGVVLEGNGLYIVT 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1958677438 441 EFMERGCLLNFLRQR-QGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05039    80 EYMAKGSLVDYLRSRgRAVITRKDQLGFALDVCEGMEYLESKKFVHRDL 128

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine kinase Bmx is expressed in the endothelium of large arteries, fetal endocardium, adult endocardium of the left ventricle, bone marrow, lung, testis, granulocytes, myeloid cell lines, and prostate cell lines. Bmx is involved in the regulation of Rho and serum response factor (SRF). Bmx has been shown to interact with PAK1, PTK2, PTPN21, and RUFY1. 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. 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. It is not present in Txk and the type 1 splice form of the Drosophila homolog. 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. 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 239 NLDQYEWYCRNTNRSKAEQLLRTEDKEGGFMVRDSSQPGLYTVSLYTKFGGEGSSGFRHYHIKETATSpkKYYLAEKHAF 318
Cdd:cd10399     2 NLDAYDWFAGNISRSQSEQLLRQKGKEGAFMVRNSSQVGMYTVSLFSKAVNDKKGTVKHYHVHTNAEN--KLYLAENYCF 79

                          90       100
                  ....*....|....*....|....*..
gi 1958677438 319 GSIPEIIEYHKHNAAGLVTRLRYPVST 345
Cdd:cd10399    80 DSIPKLIHYHQHNSAGMITRLRHPVST 106

Catalytic domain of the Protein Tyrosine Kinases, Lymphocyte-specific kinase and Blk; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Lck and Blk are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Blk is expressed specifically in B-cells. It is involved in pre-BCR (B-cell receptor) signaling. 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 Lck/Blk 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 1958677438 360 KWEINPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQkPIYIV 439
Cdd:cd05067     1 EWEVPRETLKLVERLGAGQFGEVWMGYYNGHTKVAIKSLKQGSMSPDAFLAEANLMKQLQHQRLVRLYAVVTQE-PIYII 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1958677438 440 TEFMERGCLLNFLRQRQGH-FSRDVLLSMCQDVCEGMEYLERNSFIHRDLVRPGRSVHKFLWCQV 503
Cdd:cd05067    80 TEYMENGSLVDFLKTPSGIkLTINKLLDMAAQIAEGMAFIEERNYIHRDLRAANILVSDTLSCKI 144

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 1958677438 372 RELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQkPIYIVTEFMERGCLLNF 451
Cdd:cd14203     1 VKLGQGCFGEVWMGTWNGTTKVAIKTLKPGTMSPEAFLEEAQIMKKLRHDKLVQLYAVVSEE-PIYIVTEFMSKGSLLDF 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1958677438 452 LRQRQGHFSR-DVLLSMCQDVCEGMEYLERNSFIHRDLVRPGRSVHKFLWCQV 503
Cdd:cd14203    80 LKDGEGKYLKlPQLVDMAAQIASGMAYIERMNYIHRDLRAANILVGDNLVCKI 132

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 1958677438 361 WEINPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVT 440
Cdd:cd05072     2 WEIPRESIKLVKKLGAGQFGEVWMGYYNNSTKVAVKTLKPGTMSVQAFLEEANLMKTLQHDKLVRLYAVVTKEEPIYIIT 81

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958677438 441 EFMERGCLLNFLRQRQGhfSRDVL---LSMCQDVCEGMEYLERNSFIHRDLVRPGRSVHKFLWCQV 503
Cdd:cd05072    82 EYMAKGSLLDFLKSDEG--GKVLLpklIDFSAQIAEGMAYIERKNYIHRDLRAANVLVSESLMCKI 145

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 1958677438 355 GFSYDKWEINPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQk 434
Cdd:cd05069     1 GLAKDAWEIPRESLRLDVKLGQGCFGEVWMGTWNGTTKVAIKTLKPGTMMPEAFLQEAQIMKKLRHDKLVPLYAVVSEE- 79

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 435 PIYIVTEFMERGCLLNFLRQRQG-HFSRDVLLSMCQDVCEGMEYLERNSFIHRDLVRPGRSVHKFLWCQV 503
Cdd:cd05069    80 PIYIVTEFMGKGSLLDFLKEGDGkYLKLPQLVDMAAQIADGMAYIERMNYIHRDLRAANILVGDNLVCKI 149

Catalytic domain of the Protein Tyrosine Kinase, Fyn; PTKs catalyze the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Fyn and Yrk are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases. 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 Fyn/Yrk subfamily is part of a larger superfamily that includes the catalytic domains of other kinases such as serine/threonine kinases, RIO kinases, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677438 359 DKWEINPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTqQKPIYI 438
Cdd:cd05070     2 DVWEIPRESLQLIKRLGNGQFGEVWMGTWNGNTKVAIKTLKPGTMSPESFLEEAQIMKKLKHDKLVQLYAVVS-EEPIYI 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958677438 439 VTEFMERGCLLNFLRQRQGH-FSRDVLLSMCQDVCEGMEYLERNSFIHRDLVRPGRSVHKFLWCQV 503
Cdd:cd05070    81 VTEYMSKGSLLDFLKDGEGRaLKLPNLVDMAAQVAAGMAYIERMNYIHRDLRSANILVGNGLICKI 146

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 1958677438 359 DKWEINPSELTFMRELGSGLFGVVRLGKWRAQYKVAIKAIREGAMCEEDFIEEAKVMMKLTHPKLVQLYGVCTQQkPIYI 438
Cdd:cd05073     4 DAWEIPRESLKLEKKLGAGQFGEVWMATYNKHTKVAVKTMKPGSMSVEAFLAEANVMKTLQHDKLVKLHAVVTKE-PIYI 82

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958677438 439 VTEFMERGCLLNFLRQRQGHFSR-DVLLSMCQDVCEGMEYLERNSFIHRDLVRPGRSVHKFLWCQV 503
Cdd:cd05073    83 ITEFMAKGSLLDFLKSDEGSKQPlPKLIDFSAQIAEGMAFIEQRNYIHRDLRAANILVSASLVCKI 148

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. 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 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. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. 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 1958677438 181 IVVAMYDFQATEAHDLRLERGQEYIILEKNDTHWWRARDKYGSEGYIPSNYVT 233
Cdd:cd11768     1 IVVALYDFQPIEPGDLPLEKGEEYVVLDDSNEHWWRARDKNGNEGYIPSNYVT 53

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 1958677438 372 RELGSGLFGVVRLGKWRA-QYKVAIKAIREgAMCEED---FIEEAKVMMKLTHPKLVQLYGVCTQQKPIYIVTEFMERGC 447
Cdd:cd05041     1 EKIGRGNFGDVYRGVLKPdNTEVAVKTCRE-TLPPDLkrkFLQEARILKQYDHPNIVKLIGVCVQKQPIMIVMELVPGGS 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1958677438 448 LLNFLRQRQGHFSRDVLLSMCQDVCEGMEYLERNSFIHRDL 488
Cdd:cd05041    80 LLTFLRKKGARLTVKQLLQMCLDAAAGMEYLESKNCIHRDL 120

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.