Control of fibroblast fibronectin expression and alternative splicing via the PI3K/Akt/mTOR pathway.
Publication/Presentation Date
10-1-2010
Abstract
Fibronectin (FN), a ubiquitous glycoprotein that plays critical roles in physiologic and pathologic conditions, undergoes alternative splicing which distinguishes plasma FN (pFN) from cellular FN (cFN). Although both pFN and cFN can be incorporated into the extracellular matrix, a distinguishing feature of cFN is the inclusion of an alternatively spliced exon termed EDA (for extra type III domain A). The molecular steps involved in EDA splicing are well-characterized, but pathways influencing EDA splicing are less clear. We have previously found an obligate role for inhibition of the tumor suppressor phosphatase and tensin homologue on chromosome 10 (PTEN), the primary regulator of the PI3K/Akt pathway, in fibroblast activation. Here we show TGF-beta, a potent inducer of both EDA splicing and fibroblast activation, inhibits PTEN expression and activity in mesenchymal cells, corresponding with enhanced PI3K/Akt signaling. In pten(-/-) fibroblasts, which resemble activated fibroblasts, inhibition of Akt attenuated FN production and decreased EDA alternative splicing. Moreover, inhibition of mammalian target of rapamycin (mTOR) in pten(-/-) cells also blocked FN production and EDA splicing. This effect was due to inhibition of Akt-mediated phosphorylation of the primary EDA splicing regulatory protein SF2/ASF. Importantly, FN silencing in pten(-/-) cells resulted in attenuated proliferation and migration. Thus, our results demonstrate that the PI3K/Akt/mTOR axis is instrumental in FN transcription and alternative splicing, which regulates cell behavior.
Volume
316
Issue
16
First Page
2644
Last Page
2653
ISSN
1090-2422
Published In/Presented At
White, E. S., Sagana, R. L., Booth, A. J., Yan, M., Cornett, A. M., Bloomheart, C. A., Tsui, J. L., Wilke, C. A., Moore, B. B., Ritzenthaler, J. D., Roman, J., & Muro, A. F. (2010). Control of fibroblast fibronectin expression and alternative splicing via the PI3K/Akt/mTOR pathway. Experimental cell research, 316(16), 2644–2653. https://doi.org/10.1016/j.yexcr.2010.06.028
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
20615404
Department(s)
Administration and Leadership
Document Type
Article