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

161 Citations (Scopus)

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 2007
Externally publishedYes

Fingerprint

Anoikis
Focal Adhesion Protein-Tyrosine Kinases
Myofibroblasts
Transforming Growth Factors
Phenotype
p38 Mitogen-Activated Protein Kinases
Fibroblast Growth Factor 1
Proto-Oncogene Proteins c-akt
Survival
Cytostatic Agents
Phosphatidylinositol 3-Kinases
Integrins
Protein Kinases
Neoplasms
Fibrosis
Apoptosis
Cytokines
Lung

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts. / Horowitz, Jeffrey C.; Rogers, David S.; Sharma, Vishal; Vittal, Ragini; White, Eric S.; Cui, Zongbin; Thannickal, Victor J.

In: Cellular Signalling, Vol. 19, No. 4, 04.2007, p. 761-771.

Research output: Contribution to journalArticle

Horowitz, Jeffrey C. ; Rogers, David S. ; Sharma, Vishal ; Vittal, Ragini ; White, Eric S. ; Cui, Zongbin ; Thannickal, Victor J. / Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts. In: Cellular Signalling. 2007 ; Vol. 19, No. 4. pp. 761-771.
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AU - Horowitz, Jeffrey C.

AU - Rogers, David S.

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AU - Vittal, Ragini

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AU - Cui, Zongbin

AU - Thannickal, Victor J.

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N2 - 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.

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