Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src

Giulio Superti-Furga, Stefano Fumagalli, Manfred Koegl, Sara Courtneidge, Giulio Draetta

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

The protein tyrosine kinase c-Src is negatively regulated by phosphorylation of Tyr527 in its carboxy-terminal tail. A kinase that phosphorylates Tyr527, called Csk, has recently been identified. We expressed c-Src in yeast to test the role of the SH2 and SH3 domains of Src in the negative regulation exerted by Tyr527 phosphorylation. Inducible expression of c-Src in Schizosaccharomyces pombe caused cell death. Co-expression of Csk counteracted this effect. Src proteins mutated in either the SH2 or SH3 domain were as lethal as wild type c-Src, but were insensitive to Csk, even though they were substrates for Csk in vivo. Peptide binding experiments revealed that Src proteins with mutant SH3 domains adopted a conformation in which the SH2 domain was not interacting with the tail. These data support the model of an SH2 domain-phosphorylated tail interaction repressing c-Src activity, but expand it to include a role for the SH3 domain. We propose that the SH3 domain contributes to the maintenance of the folded, inactive configuration of the Src molecule by stabilizing the SH2 domain-phosphorylated tail interaction. Moreover, the system we describe here allows for further study of the regulation of tyrosine kinases in a neutral background and in an organism amenable to genetic analysis.

Original languageEnglish (US)
Pages (from-to)2625-2634
Number of pages10
JournalEMBO Journal
Volume12
Issue number7
StatePublished - 1993
Externally publishedYes

Fingerprint

Phosphorylation
src Homology Domains
Cell death
Yeast
Protein-Tyrosine Kinases
Conformations
Proteins
Phosphotransferases
Peptides
Molecules
Substrates
Experiments
Schizosaccharomyces
Mutant Proteins
Cell Death
Yeasts
Maintenance
CSK tyrosine-protein kinase

Keywords

  • Csk
  • SH2 domain
  • SH3 domain
  • Src
  • Tyrosine kinase

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

Cite this

Superti-Furga, G., Fumagalli, S., Koegl, M., Courtneidge, S., & Draetta, G. (1993). Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src. EMBO Journal, 12(7), 2625-2634.

Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src. / Superti-Furga, Giulio; Fumagalli, Stefano; Koegl, Manfred; Courtneidge, Sara; Draetta, Giulio.

In: EMBO Journal, Vol. 12, No. 7, 1993, p. 2625-2634.

Research output: Contribution to journalArticle

Superti-Furga, G, Fumagalli, S, Koegl, M, Courtneidge, S & Draetta, G 1993, 'Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src', EMBO Journal, vol. 12, no. 7, pp. 2625-2634.
Superti-Furga G, Fumagalli S, Koegl M, Courtneidge S, Draetta G. Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src. EMBO Journal. 1993;12(7):2625-2634.
Superti-Furga, Giulio ; Fumagalli, Stefano ; Koegl, Manfred ; Courtneidge, Sara ; Draetta, Giulio. / Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src. In: EMBO Journal. 1993 ; Vol. 12, No. 7. pp. 2625-2634.
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