Mechanosensors and Signal Transduction Pathways

Cell membranes, cell attachment sites, and cytoskeletal network directly experience hemodynamic forces, and most likely serve as primary mechanosensors, as was shown in pioneering work by the groups of P. Davis and J. Shyy (Davies, 1995; Shyy and Chien, 2002) [6, 7]. Cells adhere to neighboring cells and to the extracellular matrix via transmembrane receptors of cadherin (cell-to-cell) and integrin (cell-to-substrate) families. In the cytoplasmic domain, these receptors are coupled to protein complexes, which link receptors with cytoskeleton and also mediate mechanical signal transduction via activation of signaling molecules such as tyrosine (focal adhesion kinase, p60Src) kinases, serine (Erk-1,2, JNK, and p38 MAP kinases) protein kinases, inositol lipid kinases (phospholipase C), and some growth factor receptors (VEGF and PDGF receptors). Activation of mechanoreceptors triggers multiple signal cascades with ion channels (Na+ channel, K+ channel, chloride-selective channel) and heterotrimeric G-proteins (Gaq) being activated within seconds of mechanical stimulation, and protein kinases (protein kinase C, MAP kinases, nonreceptor protein tyrosine kinases) activated within minutes of stimulation. Protein kinase-mediated phosphorylation of specific cytoskeletal and cell contact proteins, other enzymes, and transcription factors induces cytoskeletal remodeling and stimulates gene expression in vascular cells. Figure 1 summarizes major signal pathways and cellular responses induced by shear stress and cyclic stretch.

Although most putative mechanosensors and mechan-otransduction pathways are stimulated by both shear stress and stretch, the nature of mechanical forces and amplitude may still differentially affect certain signaling systems. For example, shear stress exposure selectively activates small GTPase Rac, which results in peripheral translocation of actin polymerization proteins and specific cortical actin remodeling, whereas cyclic stretch stimulates small GTPase Rho without affecting Rac and induces cytoskeletal

Onset of mechano-signalinq (less then 1 min)

K+, Na+, Cl~ channel activation

,_ 7 —'_, peripheral translocation of cortactin and myosin light chain kinase (shear stress)

cMyc activation

Regulation of SSRE-dependent genes and cvtoskeletal remodeling (30 min - 6 h)

SSRE-dependent genes: ICAM-1, MCP-1, TGF(3 , tPA, eNOS

IL8 activation Focal adhesion rearrangement

Cell alignment (cyclic stretch)

Figure 1 Major signal pathways and cellular responses induced by shear stress and cyclic stretch. Activation of mechanoreceptors triggers multiple signal cascades with ion channels (Na+ channel, K+ channel, chloride-selective channel) and heterotrimeric G-proteins (Gaq) being activated within seconds of mechanical stimulation, and protein kinases (protein kinase C, MAP kinases, nonreceptor protein tyrosine kinases) activated within minutes of stimulation. Protein kinase-mediated phosphorylation of specific cytoskeletal and cell contact proteins, other enzymes, and transcription factors induces cytoskeletal remodeling and stimulates gene expression in vascular cells.

remodeling distinct from shear stress. Furthermore, most protein kinases and ion channels involved in mechano-chemical signaling exhibit amplitude-dependent activation that may alternatively regulate gene expression described hereafter.

Essentials of Human Physiology

Essentials of Human Physiology

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