Shc proteins are phosphorylated and regulated by the v-Src and v-Fps protein-tyrosine kinases.
The mammalian shc gene encodes two overlapping proteins of 46 and 52 kDa, each with a C-terminal Src homology 2 (SH2) domain and an N-terminal glycine/proline-rich sequence, that induce malignant transformation when overexpressed in mouse fibroblasts. p46shc, p52shc, and an additional 66-kDa shc gene product become highly tyrosine phosphorylated in Rat-2 cells transformed by the v-src or v-fps oncogene. Experiments using temperature-sensitive v-src and v-fps mutants indicate that Shc tyrosine phosphorylation is rapidly induced upon activation of the v-Src or v-Fps tyrosine kinases. These results suggest that Shc proteins may be directly phosphorylated by the v-Src and v-Fps oncoproteins in vivo. In cells transformed by v-src or v-fps, or in normal cells stimulated with epidermal growth factor, Shc proteins complex with a poorly phosphorylated 23-kDa polypeptide (p23). Activated tyrosine kinases therefore regulate the association of Shc proteins with p23 and may thereby control the stimulation of an Shc-mediated signal transduction pathway. The efficient phosphorylation of Shc proteins and the apparent induction of their p23-binding activity in v-src- and v-fps-transformed cells are consistent with the proposition that the SH2-containing Shc polypeptides are biologically relevant substrates of the oncogenic v-Src and v-Fps tyrosine kinases.
McGlade
J
J
Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Cheng
A
A
Pelicci
G
G
Pelicci
P G
PG
Pawson
T
T
D000818:Animals; D002461:Cell Line, Transformed; D004591:Electrophoresis, Polyacrylamide Gel; D016391:Genes, src; D008970:Molecular Weight; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D010710:Phosphates / Q000378:metabolism; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats
D016761:Oncogene Proteins v-fos; D010710:Phosphates; D010750:Phosphoproteins; D010761:Phosphorus Radioisotopes; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src)