Activation of the focal adhesion kinase signaling pathway by structural alterations in the carboxyl-terminal region of c-Crk II

Agnes Zvara, J. Eduardo Fajardo, Marcela Escalante, Graham Cotton, Tom Muir, Kathrin H. Kirsch, Raymond B. Birge

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


The Crk II adaptor protein encodes an SH2/SH3-domain containing adaptor protein with an SH2-SH3-SH3 domain structure that transmits signals from tyrosine kinases. The two SH3 domains are separated by a 54 amino acid linker region, whose length is highly conserved in xenopus, chicken, and mamalian Crk II proteins. To gain a better understanding into the role of the C-terminal region of Crk, we generated a series of C-terminal SH3 domain and SH3 linker mutants and examined their role in tyrosine kinase pathways. Expression of point mutations in the C-terminal SH3 domain (W276K Crk), at the tyrosine phosphorylation site (Y222F Crk II), or truncation of the entire C-terminus (Crk I or Crk Δ242), all increased c-Abl binding to the N-terminal SH3 domain of Crk and, where relevant, increased Tyr222 phosphorylation. Deletion analysis of c-Crk II also revealed the presence of a C-terminal segment important for trans-activation of FAK. Such mutants, Crk Δ255 or Crk Δ242 Extended Linker (Crk Δ242|EL|), characterized by a disruption in the SH3 linker/C-terminal SH3 boundary, induced robust hyperphosphorylation of focal adhesion kinase (FAK) on Tyr397, hyperphosphorylation of focal adhesion proteins p130cas and paxillin and increased focal adhesion formation in NIH3T3 cells. The effects of Crk Δ242|EL| could be abrogated by co-expression of dominant negative c-Src or the protein tyrosine phosphatase PTP - PEST, but not by dominant negative Abl. Our results suggest that the C-terminal region of Crk contains negative regulatory elements important for both Abl and FAK dependent signal pathways, and offers a paradigm for an autoinhibitory region in the SH3 linker/C-terminal SH3 domain.

Original languageEnglish (US)
Pages (from-to)951-961
Number of pages11
Issue number8
StatePublished - Feb 22 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Cancer Research


  • Adaptor proteins
  • C-terminal SH3 domain
  • Crk
  • Focal adhesion kinase
  • SH3 linker region
  • Tyrosine phosphorylation


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