Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Jeffrey C. Horowitz, David S. Rogers, Vishal Sharma, Ragini Vittal, Eric S. White, Zongbin Cui, Victor J. Thannickal

Research output: Contribution to journalArticle

164 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/anti-apoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these pro-survival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

Original languageEnglish (US)
Pages (from-to)761-771
Number of pages11
JournalCellular Signalling
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2007

Keywords

  • Anoikis
  • Apoptosis
  • Fibroblasts
  • Focal Adhesion Kinase
  • Protein kinase B
  • SMAD proteins
  • Transforming growth factor-beta
  • p38 MAPK

ASJC Scopus subject areas

  • Cell Biology

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