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© The Rockefeller University Press, 0021-9525/1999/10/401/ $5.00
The Journal of Cell Biology, Volume 147, Number 2, October 18, 1999 401-416

Original Article

Integrin {alpha}2ß1 Mediates Isoform-specific Activation of p38 and Upregulation of Collagen Gene Transcription by a Mechanism Involving the {alpha}2 Cytoplasmic Tail

Johanna Ivaskaa, Hilkka Reunanenc, Jukka Westermarcka, Leeni Koivistoa, Veli-Matti Kähäria,b, and Jyrki Heinoa,c
a MediCity Research Laboratory, Department of Medical Biochemistry, University of Turku, FIN-20520 Turku
b Department of Dermatology, Turku University Central Hospital, FIN 20520 Turku
c Department of Biological and Environmental Science, University of Jyväskylä, FIN-40351 Jyväskylä, Finland

Correspondence to: Jyrki Heino, MediCity Research Laboratory, University of Turku, Tykistökatu 6A, FIN-20520 Turku, Finland. Tel:358-2-333-7005 Fax:358-2-333-7000 E-mail:jyrki.heino{at}utu.fi.

Two collagen receptors, integrins {alpha}1ß1 and {alpha}2ß1, can regulate distinct functions in cells. Ligation of {alpha}1ß1, unlike {alpha}2ß1, has been shown to result in recruitment of Shc and activation of the Ras/ERK pathway. To identify the downstream signaling molecules activated by {alpha}2ß1 integrin, we have overexpressed wild-type {alpha}2, or chimeric {alpha}2 subunit with {alpha}1 integrin cytoplasmic domain in human osteosarcoma cells (Saos-2) lacking endogenous {alpha}2ß1. The chimeric {alpha}2/{alpha}1 chain formed a functional heterodimer with ß1. In contrast to {alpha}2/{alpha}1 chimera, forced expression of {alpha}2 integrin resulted in upregulation of {alpha}1 (I) collagen gene transcription in response to three-dimensional collagen, indicating that the cytoplasmic domain of {alpha}2 integrin was required for signaling. Furthermore, signals mediated by {alpha}2ß1 integrin specifically activated the p38{alpha} isoform, and selective p38 inhibitors blocked upregulation of collagen gene transcription. Dominant negative mutants of Cdc42, MKK3, and MKK4 prevented {alpha}2ß1 integrin–mediated activation of p38{alpha}. RhoA had also some inhibitory effect, whereas dominant negative Rac was not effective. Our findings show the isoform-specific activation of p38 by {alpha}2ß1 integrin ligation and identify Cdc42, MKK3, and MKK4 as possible downstream effectors. These observations reveal a novel signaling mechanism of {alpha}2ß1 integrin that is distinct from ones previously described for other integrins.

Key Words: collagen, integrin, cytoplasmic domain, p38 MAPK


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