101. Integrin α2β1 Mediates Isoform-Specific Activation of p38 and Upregulation of Collagen Gene Transcription by a Mechanism Involving the α2 Cytoplasmic Tail
- Author
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Johanna Ivaska, Veli-Matti Kähäri, Jyrki Heino, Hilkka Reunanen, Leeni Koivisto, and Jukka Westermarck
- Subjects
collagen ,Integrins ,Receptors, Collagen ,Transcription, Genetic ,integrin ,Integrin ,cytoplasmic domain ,CDC42 ,Biology ,p38 MAPK ,Transfection ,CD49c ,p38 Mitogen-Activated Protein Kinases ,Collagen receptor ,Tumor Cells, Cultured ,Humans ,Protein Isoforms ,Cell Biology ,Molecular biology ,Cell biology ,Up-Regulation ,Enzyme Activation ,Integrin alpha M ,biology.protein ,Integrin, beta 6 ,Original Article ,Signal transduction ,Mitogen-Activated Protein Kinases ,ITGA6 ,Signal Transduction - Abstract
Two collagen receptors, integrins alpha1beta1 and alpha2beta1, can regulate distinct functions in cells. Ligation of alpha1beta1, unlike alpha2beta1, has been shown to result in recruitment of Shc and activation of the Ras/ERK pathway. To identify the downstream signaling molecules activated by alpha2beta1 integrin, we have overexpressed wild-type alpha2, or chimeric alpha2 subunit with alpha1 integrin cytoplasmic domain in human osteosarcoma cells (Saos-2) lacking endogenous alpha2beta1. The chimeric alpha2/alpha1 chain formed a functional heterodimer with beta1. In contrast to alpha2/alpha1 chimera, forced expression of alpha2 integrin resulted in upregulation of alpha1 (I) collagen gene transcription in response to three-dimensional collagen, indicating that the cytoplasmic domain of alpha2 integrin was required for signaling. Furthermore, signals mediated by alpha2beta1 integrin specifically activated the p38alpha isoform, and selective p38 inhibitors blocked upregulation of collagen gene transcription. Dominant negative mutants of Cdc42, MKK3, and MKK4 prevented alpha2beta1 integrin-mediated activation of p38alpha. RhoA had also some inhibitory effect, whereas dominant negative Rac was not effective. Our findings show the isoform-specific activation of p38 by alpha2beta1 integrin ligation and identify Cdc42, MKK3, and MKK4 as possible downstream effectors. These observations reveal a novel signaling mechanism of alpha2beta1 integrin that is distinct from ones previously described for other integrins.
- Published
- 1999