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Roles of mitogen-activated protein kinase and phosphoinositide 3'-kinase in ErbB2/ErbB3 coreceptor-mediated heregulin

Ulka Vijapurkar1, Myong-Soo Kim, John G Koland

  • 1Department of Pharmacology, The University of Iowa, College of Medicine, Iowa City, IA 52242-1109, USA.

Experimental Cell Research
|March 26, 2003
PubMed

Insights

The ErbB2/HER2 and ErbB3/HER3 coreceptor complex activates both MAPK and PI 3-kinase pathways. PI 3-kinase signaling is crucial for heregulin-induced cell transformation, while both pathways contribute to mitogenesis.

Area of Science:

  • Cellular signaling pathways
  • Receptor tyrosine kinases
  • Oncogenesis

Background:

  • ErbB2/HER2 and ErbB3/HER3 form a heregulin coreceptor complex.
  • This complex activates mitogen-activated protein kinase (MAPK) and phosphoinositide (PI) 3-kinase signaling pathways.
  • Understanding the distinct roles of these pathways in cell signaling is crucial.

Purpose of the Study:

  • To investigate the activation of MAPK and PI 3-kinase signaling by the ErbB2/ErbB3 coreceptor in response to heregulin.
  • To determine the relative contributions of these pathways to the mitogenic and transforming potentials of the activated coreceptor.

Main Methods:

  • Generated ErbB3 variants with mutations in Shc-binding and PI 3-kinase-binding sites.
  • Expressed wild-type and mutant ErbB3 proteins with ErbB2 in NIH-3T3 cells to form functional coreceptors.
  • Assessed MAPK and PI 3-kinase pathway activation, cyclin D1 expression, and cellular transformation in response to heregulin.

Main Results:

  • The ErbB2/ErbB3 coreceptor activates both MAPK and PI 3-kinase pathways.
  • Mutant coreceptors selectively activated either PI 3-kinase or MAPK, or neither.
  • Elimination of either pathway reduced mitogenic response; PI 3-kinase pathway was critical for cell transformation.

Conclusions:

  • Both MAPK and PI 3-kinase pathways contribute to heregulin-induced mitogenesis.
  • The PI 3-kinase pathway plays a predominant role in heregulin-mediated cellular transformation.
  • Targeting the PI 3-kinase pathway may be a strategy for inhibiting ErbB2/ErbB3-driven oncogenesis.

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