β1 Integrin Regulates Fibroblast Viability during Collagen Matrix Contraction through a Phosphatidylinositol 3-Kinase/Akt/Protein Kinase B Signaling Pathway

Abstract

Integrins regulate cell viability through their interaction with the extracellular matrix. Integrins can sense mechanical forces arising from the matrix and convert these stimuli to chemical signals capable of modulating intracellular signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is a major regulator of cell survival. It is not known, however, whether integrins, acting as mechanoreceptors, regulate cell survival via the PI3K/Akt pathway. Here, we show that in response to a matrix-derived mechanical stimulus, ␤ 1 integrin regulated cell viability by regulating Akt activity in a PI3K-dependent fashion. To accomplish this, we employed fibroblasts cultured in collagen gels. During contraction of collagen matrices, fibroblasts underwent apoptosis. We demonstrate that ligation of ␤ 1 integrin with anti-␤ 1 integrin antibodies protected fibroblasts from apoptosis. The nature of the survival signal activated by ␤ 1 integrin engagement with antibody was mediated by PI3K acting through Akt/protein kinase B. We show that Akt phosphorylation decreased during collagen contraction and that this decrease correlated precisely with the onset of fibroblast apoptosis. Fibroblasts transfected with constitutively active PI3K displayed increased Akt phosphorylation and were protected from anoikis and collagen gel contraction-induced apoptosis. Our data identify a novel role for ␤ 1 integrin in regulating fibroblast viability through a PI3K/Akt/protein kinase B signaling pathway in response to a matrix-derived mechanical stimulus.

A Functionally Relevant Conformational Epitope on the CD9 Tetraspanin Depends on the Association with Activated β1Integrin

“…Signal transduction through integrins in many different cellular systems involves the activation of PI3K, an event which in turn regulates many other important cell functions such as cell survival and apoptosis and the activity of Rho family small GTPases, which control cell morphology, polarization, and migration (26,47,55,56). So far, however, very few reports have described the implication of tetraspanins in integrin-mediated signal transduction.…”

Epithelium–mesenchyme compartment interaction and oncosis on chemotherapy-induced hair damage

“…33,34 This activity requires that both matrix cells and fibroblasts maintain close contacts via the ECM. 34,35 Therefore, the involution of matrix cells may by assisted by the reduction of the physical relationships between FP cells and the matrix, the direct action of DXR and the mechanical stimuli arising from CTS retraction.…”

Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3β (GSK-3β) in vitro

“…b1-integrin-linked kinase functioning in a phosphatidylinositol-3 kinase (PI3-K)-dependent manner (Delcommenne et al, 1998) is able to stimulate protein kinase Ba/Akt (PKBa/Akt) and glycogen synthase kinase-3b (GSK-3b) (Troussard et al, 1999). These events proceed in inhibition of apoptosis by phosphorylating and inactivating apoptotic factors such as caspase-9 and Bad through PKBa/Akt (Datta et al, 1997;Khwaja et al, 1997;Tian et al, 2002) and cell cycle progression via prevention of cyclin D1 proteolysis (Diehl et al, 1998) and gene expression via AP-1 or NF-kB through GSK-3b (Troussard et al, 1999;Hoeflich et al, 2000).…”