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Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment

Si Qing Zhang1, Wentian Yang, Maria I Kontaridis

  • 1Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, MA 02115 USA.

Molecular Cell
|February 18, 2004
PubMed

Insights

The protein-tyrosine phosphatase Shp2 regulates Src family kinases (SFKs) by controlling Csk access to SFKs. Shp2 deficiency impairs SFK substrate phosphorylation, affecting Ras/Erk signaling and cell functions.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Biochemistry

Background:

  • Shp2 is a protein-tyrosine phosphatase crucial for growth factor and integrin signaling.
  • Shp2 mutations are linked to developmental disorders and cancer.
  • Shp2's precise mechanism of action and substrates remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism by which Shp2 influences signaling pathways.
  • To identify Shp2 substrates and downstream effectors.
  • To investigate Shp2's role in regulating Src family kinases (SFKs).

Main Methods:

  • Analysis of Shp2-deficient cells.
  • Phosphorylation site analysis of SFKs and their regulators (PAG/Cbp).
  • Assessment of SFK substrate phosphorylation, including Plcgamma1.
  • Evaluation of Ras and Erk activation.
  • Examination of cellular phenotypes such as cell spreading and motility.

Main Results:

  • Shp2 promotes SFK activation by regulating PAG/Cbp phosphorylation, which controls Csk access to SFKs.
  • Shp2 deficiency results in hyperphosphorylated inhibitory C-terminal tyrosines on SFKs.
  • Multiple SFK substrates, including Plcgamma1, show decreased phosphorylation in Shp2-deficient cells.
  • Impaired Plcgamma1 phosphorylation leads to defective endomembrane Ras activation and reduced Erk activation.
  • Other SFK substrate alterations contribute to defects in cell spreading, stress fibers, focal adhesions, and motility.

Conclusions:

  • Shp2 is a key regulator of SFK activity through modulation of Csk-mediated inhibitory phosphorylation.
  • Shp2's role extends beyond Ras/Erk activation, impacting a broader network of SFK-dependent cellular processes.
  • Understanding Shp2's function provides insights into developmental abnormalities and malignancy associated with its mutations.

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