The role of focal adhesion kinase-phosphatidylinositol 3-kinase-Akt signaling in hepatic stellate cell proliferation and type I collagen expression

Shimon Reif, Alon Lang, Jeffery N. Lindquist, Yutaka Yata, Erwin Gäbele, Andrew Scanga, David A. Brenner, Richard A. Rippe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

263 Scopus citations

Abstract

Following a fibrogenic stimulus, the hepatic stellate cell (HSC) undergoes a complex activation process associated with increased cell proliferation and excess deposition of type I collagen. The focal adhesion kinase (FAK)-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is activated by platelet-derived growth factor (PDGF) in several cell types. We investigated the role of the FAK-PI3K-Akt pathway in HSC activation. Inhibition of FAK activity blocked HSC migration, cell attach. ment, and PDGF-induced PI3K and Akt activation. Both serum- and PDGF-induced Akt phosphorylation was inhibited by LY294002, an inhibitor of PI3K. A constitutively active form of Akt stimulated HSC proliferation in serum-starved HSCs, whereas LY294002 and dominant-negative forms of Akt and FAK inhibited PDGF-induced proliferation. Transforming growth factor-β, an inhibitor of HSC proliferation, did not block PDGF-induced Akt phosphorylation, suggesting that transforming growth factor-β mediates its antiproliferative effect downstream of Akt. Expression of type I collagen protein and α1(I) collagen mRNA was increased by Akt activation and inhibited when PI3K activity was blocked. Therefore, FAK is important for HSC migration, cell attachment, and PDGF-induced cell proliferation. PI3K is positioned downstream of FAK. Signals for HSC proliferation are transduced through FAK, PI3K, and Akt. Finally, expression of type I collagen is regulated by the PI3K-Akt signaling pathway.

Original languageEnglish
Pages (from-to)8083-8090
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number10
DOIs
StatePublished - 7 Mar 2003
Externally publishedYes

Funding

FundersFunder number
National Institute on Alcohol Abuse and AlcoholismP60AA011605, R01AA010459
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK034987

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