From Integrin to Mitochondria

Abstract

Integrin cross-linking can stimulate several cellular signaling pathways, resulting in cytoskeletal reorganization and gene expression. Werner and Werb investigated how integrin cross-linking, specifically integrins containing the α5 subunit, can trigger an increase in reactive oxygen species (ROS) that leads to the stimulation of the NF-κB transcription factor and expression of the matrix metalloproteinase-1 and collagenase-1 gene CL-1 . Cross-linking of the α5 integrins with an antibody stimulated a transient increase in extracellular and intracellular hydrogen peroxide (H 2 O 2 ). Increased H 2 O 2 was also observed in cells expressing constitutively active forms of the guanosine triphosphatase Rac or RhoA, but not Cdc42. The integrin-stimulated increase in H 2 O 2 required activation of Rac and could be blocked by a Rac dominant-negative mutant. The activation of NF-κB and transcription of CL-1 was blocked by expression of Rac with a mutation in position L37. The increased H 2 O 2 was inhibited if the mitochondrial respiratory chain was inhibited. To assess whether dissipation of the mitochondrial membrane potential was involved in the activation of CL-1 expression, cells were sorted into two populations: those that showed a dissipation of the mitochondrial membrane potential in response to integrin activation and those that did not. Only the cells in which the potential had been dissipated in response to the integrin activation later showed increased expression of CL-1 . Despite transient dissipation of the mitochondrial membrane potential, the integrin-cross-linked cells did not undergo apoptosis or appear to undergo the mitochondrial permeability transition. However, overexpression of the antiapoptotic protein Bcl-2 inhibited integrin-stimulated expression of CL-1 , suggesting that Bcl-2 may be a modulator of this process in addition to its role in apoptosis. E. Werner, Z. Werb, Integrins engage mitochondrial function for signal transduction by a mechanism dependent on Rho GTPases. J. Cell Biol. 158 , 357-368 (2002). [Abstract] [Full Text]