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© The Rockefeller University Press,
0021-9525/1999//401 $5.00
The Journal of Cell Biology, Volume 147, Number 2,
, 1999 401-416
Original Article |
Integrin
2β1 Mediates Isoform-Specific Activation of p38 and Upregulation of Collagen Gene Transcription by a Mechanism Involving the
2 Cytoplasmic Tail
jyrki.heino{at}utu.fi
Two collagen receptors, integrins
1β1 and
2β1, can regulate distinct functions in cells. Ligation of
1β1, unlike
2β1, has been shown to result in recruitment of Shc and activation of the Ras/ERK pathway. To identify the downstream signaling molecules activated by
2β1 integrin, we have overexpressed wild-type
2, or chimeric
2 subunit with
1 integrin cytoplasmic domain in human osteosarcoma cells (Saos-2) lacking endogenous
2β1. The chimeric
2/
1 chain formed a functional heterodimer with β1. In contrast to
2/
1 chimera, forced expression of
2 integrin resulted in upregulation of
1 (I) collagen gene transcription in response to three-dimensional collagen, indicating that the cytoplasmic domain of
2 integrin was required for signaling. Furthermore, signals mediated by
2β1 integrin specifically activated the p38
isoform, and selective p38 inhibitors blocked upregulation of collagen gene transcription. Dominant negative mutants of Cdc42, MKK3, and MKK4 prevented
2β1 integrin–mediated activation of p38
. RhoA had also some inhibitory effect, whereas dominant negative Rac was not effective. Our findings show the isoform-specific activation of p38 by
2β1 integrin ligation and identify Cdc42, MKK3, and MKK4 as possible downstream effectors. These observations reveal a novel signaling mechanism of
2β1 integrin that is distinct from ones previously described for other integrins.
Key Words: collagen integrin cytoplasmic domain p38 MAPK
© 1999 The Rockefeller University Press
1.used in this paper: ECM, extracellular matrix; ERK, extracellular signal–related kinase; FAK, focal adhesion kinase; JNK, c-jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; PI-3K, phosphatidylinositol-3-kinase; PK, protein kinase
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