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A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src

Caterina Bianco1, Luigi Strizzi, Aasia Rehman

  • 1Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Cancer Research
|March 22, 2003
PubMed

Insights

Human Cripto-1 (CR-1) binds Glypican-1, activating Src kinase to promote cell growth and migration. This discovery reveals a novel signaling pathway for CR-1 independent of Nodal and ALK4.

Area of Science:

  • Molecular and Cellular Biology
  • Cancer Research
  • Developmental Biology

Background:

  • Human Cripto-1 (CR-1) is a growth factor involved in development.
  • CR-1 acts as a coreceptor with ALK4 for the Nodal signaling pathway.
  • CR-1 can activate MAPK and Akt pathways independently of Nodal and ALK4 through an unknown mechanism.

Purpose of the Study:

  • To elucidate the mechanism by which CR-1 activates signaling pathways independently of Nodal and ALK4.
  • To identify the direct binding partners of CR-1 involved in these alternative signaling pathways.
  • To determine the role of Src kinase in CR-1-mediated cellular processes.

Main Methods:

  • Co-immunoprecipitation assays to identify CR-1 binding partners.
  • Western blotting to detect activation of MAPK, Akt, and Src kinases.
  • In vitro cell transformation and migration assays using mouse mammary epithelial cells.

Main Results:

  • CR-1 specifically binds to Glypican-1, a heparan sulfate proteoglycan.
  • CR-1 binding to Glypican-1 activates the tyrosine kinase c-Src.
  • Activated Src kinase is essential for CR-1-induced cell transformation and migration.

Conclusions:

  • CR-1 utilizes Glypican-1 as a receptor to activate the Src tyrosine kinase.
  • The CR-1-Glypican-1-Src axis represents a novel signaling pathway.
  • Targeting this pathway may offer new therapeutic strategies for cancers involving CR-1.

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