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PMID: 11331299 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inhibitory role of alpha 6 beta 4-associated erbB-2 and phosphoinositide 3-kinase in keratinocyte haptotactic migration dependent on alpha 3 beta 1 integrin.

The Journal of cell biology ·Vol. 153 ·No. 3 ·2001-00-30 ·Pages 465-78

Hintermann E, Bilban M, Sharabi A, Quaranta V

Abstract

Keratinocytes and other epithelial cells express two receptors for the basement membrane (BM) extracellular matrix component laminin-5 (Ln-5), integrins alpha 3 beta 1 and alpha 6 beta 4. While alpha 3 beta 1 mediates adhesion, spreading, and migration (Kreidberg, J.A. 2000. Curr. Opin. Cell Biol. 12:548--553), alpha 6 beta 4 is involved in BM anchorage via hemidesmosomes (Borradori, L., and A. Sonnenberg. 1999. J. Invest. Dermatol. 112:411--418). We investigated a possible regulatory interplay between alpha 3 beta 1 and alpha 6 beta 4 in cell motility using HaCaT keratinocytes as a model. We found that alpha 6 beta 4 antibodies inhibit alpha 3 beta 1-mediated migration on Ln-5, but only when migration is haptotactic (i.e., spontaneous or stimulated by alpha 3 beta 1 activation), and not when chemotactic (i.e., triggered by epidermal growth factor receptor). Inhibition of migration by alpha 6 beta 4 depends upon phosphoinositide 3-kinase (PI3-K) since it is abolished by PI3-K blockers and by dominant-negative PI3-K, and constitutively active PI3-K prevents haptotaxis. In HaCaT cells incubated with anti-alpha 6 beta 4 antibodies, activation of PI3-K is mediated by alpha 6 beta 4-associated erbB-2, as indicated by erbB-2 autophosphorylation and erbB-2/p85 PI3-K coprecipitation. Furthermore, dominant-negative erbB-2 abolishes inhibition of haptotaxis by anti-alpha 6 beta 4 antibodies. These results support a model whereby (a) haptotactic cell migration on Ln-5 is regulated by concerted action of alpha 3beta 1 and alpha 6 beta 4 integrins, (b) alpha 6 beta 4-associated erbB-2 and PI3-K negatively affect haptotaxis, and (c) chemotaxis on Ln-5 is not affected by alpha 6 beta 4 antibodies and may require PI3-K activity. This model could be of general relevance to motility of epithelial cells in contact with BM.

MeSH Terms
Antigens, Surface/metabolism Cell Adhesion Molecules/metabolism Cell Line Cell Movement/physiology Chemotaxis/physiology Humans Integrin alpha3beta1 Integrin alpha6beta4 Integrins/metabolism Keratinocytes/physiology Phosphatidylinositol 3-Kinases/metabolism Receptor, ErbB-2/metabolism Receptors, Laminin Signal Transduction
Chemicals
Antigens, Surface Cell Adhesion Molecules Integrin alpha3beta1 Integrin alpha6beta4 Integrins Receptors, Laminin kalinin Phosphatidylinositol 3-Kinases Receptor, ErbB-2
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Hintermann Edith
Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Bilban Martin
Sharabi Andrew
Quaranta Vito
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.153.3.465
Published
2001-00-30
Pages
465-78
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2190561
Subset
IM
Grants
NCI NIH HHS · CA 47858 · United States
NIGMS NIH HHS · GM46902 · United States
External Links
PubMed source DOI: 10.1083/jcb.153.3.465 PMC Full Text View journal details
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