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Differential utilization and localization of ErbB receptor tyrosine kinases in skin compared to normal and malignant

S W Stoll1, S Kansra, S Peshick

  • 1Department of Dermatology, University of Michigan Medical Center, 1500 East Medical CenterDrive, Ann Arbor, MI 48109, USA.

Neoplasia (New York, N.Y.)
|September 26, 2001
PubMed

Insights

Multiple ErbB receptor tyrosine kinases (RTKs) regulate skin cell physiology. ErbB1 drives proliferation and survival, while ErbB2 mediates differentiation signals, with ErbB2 sequestration potentially driving cancer in A431 cells.

Area of Science:

  • Dermatology
  • Molecular Biology
  • Cell Signaling

Background:

  • Heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA induction in mouse skin is blocked by pan-ErbB receptor tyrosine kinase (RTK) inhibitors.
  • Genetic ablation of ErbB1 does not block HB-EGF induction, suggesting involvement of multiple ErbB species in skin physiology.

Purpose of the Study:

  • To investigate the roles of different ErbB receptor tyrosine kinases (RTKs) in human skin physiology and cancer.
  • To elucidate the specific signaling pathways mediated by ErbB1 and ErbB2 in keratinocytes and A431 carcinoma cells.

Main Methods:

  • Analysis of ErbB receptor expression (ErbB1, ErbB2, ErbB3, ErbB4) in human skin, keratinocytes, and A431 cells.
  • Assessment of tyrosine phosphorylation in response to heregulin in A431 and MDA-MB-453 cells.
  • Evaluation of keratinocyte proliferation using selective ErbB1-RTK inhibitors.

Main Results:

  • Human skin, keratinocytes, and A431 cells express ErbB1, ErbB2, and ErbB3, but not ErbB4.
  • ErbB2 and ErbB3 are highly expressed in skin and A431 cells, but heregulin is inactive in A431 cells.
  • ErbB1 is crucial for keratinocyte proliferation, while ErbB2 mediates differentiation signals; intracellular ErbB2 sequestration in A431 cells may contribute to their malignant phenotype.

Conclusions:

  • ErbB1 and ErbB2 play distinct roles in skin keratinocyte signaling: ErbB1 for proliferation/survival and ErbB2 for differentiation.
  • Differential localization and signaling of ErbB receptors contribute to normal skin function and potentially to cancer development.

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