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Published 29 September 2003. doi:10.1083/jcb.200305006
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© The Rockefeller University Press, 0021-9525/2003/9/1189 $5.00
The Journal of Cell Biology, Volume 162, Number 7, 1189-1196

Report

Compartmentalization of integrin {alpha}6ß4 signaling in lipid rafts



Laurent Gagnoux-Palacios1, Michael Dans1, Wouter van't Hof1, Agnese Mariotti1, Angela Pepe1, Guerrino Meneguzzi2, Marilyn D. Resh1 and Filippo G. Giancotti1

1 Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
2 INSERM U385, School of Medicine, University of Nice, 06107 Nice, France

Address correspondence to Filippo G. Giancotti, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, Box 216, 1275 York Avenue, New York, NY 10021. Tel.: (212) 639-6998. Fax: (212) 794-6236. email: f-giancotti{at}ski.mskcc.org

Integrin {alpha}6ß4 signaling proceeds through Src family kinase (SFK)–mediated phosphorylation of the cytoplasmic tail of ß4, recruitment of Shc, and activation of Ras and phosphoinositide-3 kinase. Upon cessation of signaling, {alpha}6ß4 mediates assembly of hemidesmosomes. Here, we report that part of {alpha}6ß4 is incorporated in lipid rafts. Metabolic labeling in combination with mutagenesis indicates that one or more cysteine in the membrane-proximal segment of ß4 tail is palmitoylated. Mutation of these cysteines suppresses incorporation of {alpha}6ß4 in lipid rafts, but does not affect {alpha}6ß4-mediated adhesion or assembly of hemidesmosomes. The fraction of {alpha}6ß4 localized to rafts associates with a palmitoylated SFK, whereas the remainder does not. Ligation of palmitoylation-defective {alpha}6ß4 does not activate SFK signaling to extracellular signal–regulated kinase and fails to promote keratinocyte proliferation in response to EGF. Thus, compartmentalization in lipid rafts is necessary to couple the {alpha}6ß4 integrin to a palmitoylated SFK and promote EGF-dependent mitogenesis.

Key Words: keratinocyte; proliferation; palmitoylation; hemidesmosome; cysteine

The online version of this article includes supplemental material.

L. Gagnoux-Palacios' present address is INSERM U385, School of Medicine, University of Nice, 06107 Nice, France.

M. Dans' present address is Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104.

W. van't Hof's present address is Athersys Inc., Cleveland, OH 44115.

A. Mariotti's present address is CePO/ISREC, 1066 Epalinges, Switzerland.

Abbreviations used in this paper: [125I]IC16, 16-[125I]iodohexadecanoic acid; EGF-R, EGF receptor; ERK, extracellular signal–regulated kinase; HUVEC, human umbilical venous endothelial cell; PA-JEB, junctional epidermal bullosa with pyloric atresia; PI-3K, phosphatidylinositol-3 kinase; pSFK, palmitoylated Src family kinase; SFK, Src family kinase.


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