Tyrosine kinase signalling pathways.
Protein-tyrosine kinases act as receptors for a wide range of external signals that control the growth and differentiation of normal cells. Additionally, many retroviral and cellular oncogenes encode tyrosine kinase variants that are constitutively active. Recent evidence suggests that the intracellular targets of tyrosine kinases contain a protein module of approximately 100 amino acids, the Src homology 2 (SH2) domain. SH2 domains directly recognize tyrosine phosphorylation sites, and are thereby recruited to activated, autophosphorylated growth factor receptors. These interactions, in turn, stimulate the biochemical signalling pathways that control gene expression, cytoskeletal architecture, and cell metabolism. SH2-containing proteins frequently contain a distinct element of approximately 50 residues, the SH3 domain, that recognizes proline-rich motifs. Proteins with SH2 and SH3 domains can act as adaptors to couple tyrosine kinases to downstream targets with SH3-binding sites. A specific example of the synergistic action of SH2 and SH3 domains involves regulation of the Ras pathway by the adaptor protein Sem-5/drk/Grb2, which links tyrosine kinases to the Ras guanine nucleotide releasing protein Sos, which converts Ras to the active GTP-bound state.
Pawson
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Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000502:physiology; D011499:Protein Processing, Post-Translational; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000502:physiology; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018631:ras Proteins