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

The protein-tyrosine phosphatase Shp2 plays an essential role in growth factor and integrin signaling, and Shp2 mutations cause developmental defects and/or malignancy. Previous work has placed Shp2 upstream of Ras. However, the mechanism of Shp2 action and its substrate(s) are poorly defined. Additional Shp2 functions downstream of, or parallel to, Ras/Erk activation also are proposed. Here, we show that Shp2 promotes Src family kinase (SFK) activation by regulating the phosphorylation of the Csk regulator PAG/Cbp, thereby controlling Csk access to SFKs. In Shp2-deficient cells, SFK inhibitory C-terminal tyrosines are hyperphosphorylated, and the tyrosyl phosphorylation of multiple SFK substrates, including Plcgamma1, is decreased. Decreased Plcgamma1 phosphorylation leads to defective Ras activation on endomembranes, and may help account for impaired Erk activation in Shp2-deficient cells. Decreased phosphorylation/activation of other SFK substrates may explain additional consequences of Shp2 deficiency, including altered cell spreading, stress fibers, focal adhesions, and motility.

Pubmed ID: 14967142


  • Zhang SQ
  • Yang W
  • Kontaridis MI
  • Bivona TG
  • Wen G
  • Araki T
  • Luo J
  • Thompson JA
  • Schraven BL
  • Philips MR
  • Neel BG


Molecular cell

Publication Data

February 13, 2004

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM55279
  • Agency: NCI NIH HHS, Id: R01CA49152
  • Agency: NCI NIH HHS, Id: T32 CA81156
  • Agency: NIGMS NIH HHS, Id: T32 GM07308

Mesh Terms

  • 3T3 Cells
  • Animals
  • Down-Regulation
  • Intracellular Membranes
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases
  • Phospholipase C gamma
  • Phosphoproteins
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases
  • Protein-Tyrosine Kinases
  • Signal Transduction
  • Type C Phospholipases
  • Tyrosine
  • ras Proteins
  • src-Family Kinases