Sensing the Direction of Stress

Abstract

Many cells will respond to a tug or a nudge by activating appropriate signaling pathways that ultimately regulate gene expression. But just how cells sense such mechanical strain remains poorly understood. Kumar et al. report observations that begin to reveal previously unrecognized complexity in the sensory machinery. The authors studied responses of diaphragm muscle from mice in vitro. The diaphragm has the unusual property of experiencing mechanical load not only axially, that is, in the direction along the length of the muscle fibers, but also transversely, across the fibers. Both axial and transverse stretching activate the mitogen-activated protein kinases (MAPKs) ERK1 and ERK2, which in turn are linked to activation of p90 RSK (ribosomal protein S6 kinase) and activation of the AP1 transcription factor complex. However, transverse stretching was more effective in activating such signals than was axial stretching. The cell's capacity to detect the direction of mechanical stress was revealed in experiments with pharmacological inhibitors that interfered with specific signaling pathways. Axial stretching activated ERK1 and ERK2 by a mechanism that required signaling through phosphoinositide 3-kinase, intracellular calcium release, protein kinase C, and the MAPK kinases MEK1 or MEK2. In contrast, transverse stretching of the muscle cells activated ERKs 1and 2 in a manner that required cAMP (adenosine 3′-5′ monophosphate)-dependent protein kinase. The authors conclude that diaphragm muscles appear to have two distinct pathways leading to ERK activation and altered gene expression with each responding to mechanical stress in a particular direction. A. Kumar, I. Chaudhry, M. B. Reid, A. M. Boriek, Distinct signaling pathways are activated in response to mechanical stress applied axially and transversely to skeletal muscle fibers. J. Biol. Chem. 277 , 46493-46503 (2002). [Abstract] [Full Text]