Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts.

Abstract

Integrins, which connect the cytoskeleton to the extracellular matrix and mediate a variety of signaling cascades, may transduce mechanical stimuli into biochemical signals. We studied integrin- and matrix-dependent activation of extracellular signal-regulated kinase (ERK2), c-Jun NH2-terminal kinase (JNK1), and p38 in response to 4% static biaxial stretch in rat cardiac fibroblasts. ERK2 and JNK1, but not p38, were rapidly activated by stretch when the fibroblasts were allowed to synthesize their own matrices. When the cells were limited to specific matrix substrates, ERK2 and JNK1 were differentially activated: ERK2 was only activated when the cells were plated on fibronectin, while JNK1 was activated when the cells were plated on fibronectin, vitronectin, or laminin. Plating cells on collagen before stretching did not activate either kinase. Adhesion to all matrices was integrin-dependent because it could be blocked by inhibitors of specific integrins. ERK2 activation could be blocked with a combination of anti-alpha4 and -alpha5 antibodies and an arginine-glycine-aspartic acid (RGD) peptide, while the antibodies or peptide used separately failed to block ERK2 activation. This result suggests that at least two integrins, alpha4beta1 and an RGD-directed, non-alpha5beta1 integrin, activate ERK2 in response to mechanical stimulation. Activation of JNK1 could not be blocked with the inhibitors, suggesting that an RGD-independent integrin or integrins other than alpha4beta1 can activate JNK1 in cells adherent to fibronectin. This study demonstrates that integrins act as mechanotransducers, providing insight into potential mechanisms for in vivo responses to mechanical stimuli.

Integrins in Mechanotransduction

“…Static biaxial stretch of cardiac fibroblasts activated the MAP kinase pathways, ERK2 and c-Jun Nterminal kinase (JNK1) in an ECM-specific manner (45). ERK2 was stimulated only in cells plated on fibronectin; JNK1 was activated on fibronectin, vitronectin, or laminin; and cells on collagen did not activate any of these MAP kinases.…”

Stress signaling in Drosophila

“…It is intriguing to speculate that tension, or adhesion, sustained by cell junctions, or contractility itself, mediated by the cytoskeleton, might stimulate the JNK pathway, which then maintains the progression of cellular elongation and movement through regulated feedback mechanisms such as Puc. This so-called mechanotransduction, or coupling of cellular deformation and stretching to the signal transduction machinery, has been documented in mammalian muscle and bone cells and often leads to stimulation of stress signaling cascades (Hamada et al, 1998;Komuro et al, 1996;MacKenna et al, 1998). The source of the proposed signal may also be from tissue neighboring the LE, such as the amnioserosa, but to date, little evidence has accumulated addressing the role of the amnioserosa in DC.…”

Cyclic tensile stretch inhibition of nitric oxide release from osteoblast‐like cells is both G protein and actin‐dependent

“…In response to environmental stress, such as mechanical stress, cellular metabolism is regulated through the expression and/or activation of stress responsive molecules [18,21]. Among these molecules implicated in the stress-inducible signal transduction cascade, three distinct, but related, sets of mitogen-activated protein kinases (MAPKs) have been identified and cloned.…”