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Role of the Grb2-associated binder 1/SHP-2 interaction in cell growth and transformation

Marina Holgado-Madruga1, Albert J Wong

  • 1Department of Microbiology and Immunology, The Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10th Street, 1002 BLSB, Philadelphia, PA 19107, USA. M_Holgado_Madruga@mail.jci.tju.edu

Cancer Research
|March 18, 2004
PubMed

Insights

The Gab1/SHP-2 interaction is crucial for cell growth and transformation, mediated by a novel pathway independent of AKT or ERK signaling. Disrupting this interaction reverses the transformed phenotype, suggesting it as a therapeutic target for malignant cell growth.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Grb2-associated binder 1 (Gab1) is a docking protein activated by cytokine receptors and receptor tyrosine kinases.
  • Gab1 recruits and activates signaling molecules, enhancing cell growth and transformation downstream of the epidermal growth factor (EGF) receptor.
  • The SHP-2 phosphatase is a major binding partner of Gab1, suggesting a key role in Gab1-mediated signaling.

Purpose of the Study:

  • To investigate the role of the Gab1/SHP-2 interaction in Gab1-mediated cell growth and transformation.
  • To elucidate the downstream signaling pathways affected by the Gab1/SHP-2 interaction.
  • To determine if the Gab1/SHP-2 interaction is a potential therapeutic target for malignant cell growth.

Main Methods:

  • Engineered Gab1 cDNA with a mutated SHP-2 binding site (Gab1/DeltaSHP-2).
  • Overexpressed Gab1/DeltaSHP-2, wild-type Gab1, or an empty vector in NIH3T3 cells.
  • Analyzed tyrosine phosphorylation, phosphatidylinositol 3'-kinase recruitment, AKT and extracellular-regulated kinase 1 (ERK1) activation, c-fos promoter induction, cell proliferation, and anchorage-independent growth after EGF stimulation.

Main Results:

  • Gab1/DeltaSHP-2 exhibited higher early tyrosine phosphorylation and increased phosphatidylinositol 3'-kinase recruitment compared to wild-type Gab1.
  • Enhanced and sustained AKT activation and higher early ERK1 activation were observed in Gab1/DeltaSHP-2 cells.
  • Unexpectedly, Gab1/DeltaSHP-2 cells showed reduced c-fos induction, decreased cell proliferation, and reversion of the transformed phenotype, including increased stress fibers.

Conclusions:

  • The Gab1/SHP-2 interaction is essential for EGF-induced cell growth and transformation.
  • This interaction appears to operate through a novel pathway independent of AKT and ERK signaling.
  • Targeting the Gab1/SHP-2 interaction offers a potential strategy for inhibiting malignant cell growth.

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