Suppression of c-Src activity by C-terminal Src kinase involves the c-Src SH2 and SH3 domains: analysis with Saccharomyces cerevisiae.

Abstract

The kinase activity of c-Src is normally repressed in vertebrate cells by extensive phosphorylation of Y-527. C-terminal Src kinase (CSK) is a candidate for the enzyme that catalyzes this phosphorylation. We have used budding yeast to study the regulation of c-Src activity by CSK in intact cells. Expression of c-Src in Saccharomyces cerevisiae, which lacks endogenous c-Src and Y-527 kinases, induces a kinase-dependent growth inhibition. Coexpression of CSK in these cells results in phosphorylation of c-Src on Y-527 and suppression of the c-Src phenotype. CSK does not fully suppress the activity of c-Src mutants lacking portions of the SH2 or SH3 domains, even though these mutant proteins are phosphorylated on Y-527 by CSK both in vivo and in vitro. These results suggest that both the SH2 and SH3 domains of c-Src are required for the suppression of c-Src activity by Y-527 phosphorylation.

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…SFK proteins range in molecular mass from 52 to 62 kDa and share a conserved domain structure consisting of consecutive SH4 domain, unique domain, SH3 domain, SH2-SH3 linker, SH2 domain, SH1 (catalytic domain), and C terminal negative regulatory region. The SH3 domain contributes to substrate recruitment [110,111] and is critical for the regulation of kinase activity [112][113][114], (Fig. 4).…”

Intramolecular Regulatory Interactions in the Src Family Kinase Hck Probed by Mutagenesis of a Conserved Tryptophan Residue

“…The SH2 domains of Src kinases bind their C-terminally phosphorylated tails (3-7), and this interaction stabilizes an inactive conformation. Genetic experiments first suggested that the SH3 domain of Src was also involved in the repression of catalytic activity (15,16). The three-dimensional structures of c-Src and Hck (17)(18)(19) provide an explanation for the involvement of the Src homology domains in enzyme inhibition (Fig.…”

A novel mammalian myosin I from rat with an SH3 domain localizes to Con A-inducible, F-actin-rich structures at cell-cell contacts.

“…SH3 domains have been reported to act and interact intramolecularly and to be masked until activation exposes them for interaction with a target protein (Murphy et al, 1993;Okada et ai., 1993;Superti-Furga et al, 1993). Indeed, the myr 3 tail region exhibits proline-rich sequences that could possibly interact with the SH3 domain.…”