Biochemistry of the Src protein-tyrosine kinase: regulation by SH2 and SH3 domains.
pp60c-Srs (c-Src) is the prototype for a family of cytoplasmic protein-tyrosine kinases involved in the control of signal transduction. In addition to the enzymatic kinase domain, c-Src has several noncatalytic domains which regulate Src tyrosine kinase activity in both a positive and a negative fashion. Phosphorylation of c-Src at Tyr527 in the noncatalytic C-terminal tail is a key mechanism for repression of c-Src tyrosine kinase activity. This inhibitory phosphorylation is apparently catalyzed by another cytoplasmic tyrosine kinase (Csk). Recent evidence suggests that the c-Src SH2 domain participates in this phosphorylation-dependent repression of kinase activity through an intramolecular association with the phosphotyrosine-containing C-terminus. The SH3 domain of c-Src also negatively regulates c-Src tyrosin kinase activity, although the mechanism is as yet unknown. However, in the background of constitutively active transforming Src variants, such as a c-Src mutant with an amino acid substitution eliminating Tyr527 (527F c-Src) or the retroviral oncogene v-src product pp60v-src (v-Src), both the SH2 and SH3 domains contribute positively to the enzymatic and biological activities of the Src tyrosine kinase through interactions with Src substrates and/or cellular regulators.
Liu
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Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Pawson
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D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src)