Wayne Orr and the rest of the Ginsberg/Schwartz team have another interesting paper on the basic signaling mechanisms of adhesion and motility, this time in the journal Molecular Biology of the Cell: Matrix-specific Suppression of Integrin Activation in Shear Stress Signaling.
Orr et al. make the case for “transdominant inhibition” in endothelial cells, describing the observation that ligation of one integrin receptor type can suppress the activation of other integrins, through specific signaling pathways. They make the case for the involvement of PI(3)K, PIP3, PKA, PKC, and NFkB, and suggest that these inhibition pathways converge on the Integrin beta-tail-interacting protein Talin, in establishing patterns of dominance among ECM receptors, and thus specific matrix preferences.
One implication of this, heavily emphasized by Orr et al., is in the origin of atheroschlerosis, but it is possible that this mechanism of matrix-specificity plays a role in selection and extravasation of metastasizing cancer cells at new secondary tumor sites. In this model, Collagen may suppress fibronectin/fibrinogen(FN/FG)-associated inflammatory signaling, and conversely, FN/FG may suppress anti-inflammatory and anti-atherogenic Collagen signaling. As a main signaling component of this FN/FG-associated Collagen-suppression is inhibition of the a2b1 Integrin by PKC, PKC may be a potent pharmaceutical target to the benefit of individuals with atheroschlerosis.
This is a detailed paper, however, bringing together a wide range of very detailed data to make the above-mentioned conclusions. So I’m not quite sure how much of it to bring in. Take Figure 9, for instance, which brings together the data implicating PKCalpha in a5b1/avb3-suppression of a2b1.
That’s a lot to explain, and then I’d have to explain a great deal of the rest of the figures too. No, I’m going to leave this simple: Orr et al. make the suggestion that PKCalpha should be explored as a potential drug target for the treatment of atheroschlerosis.
- Matrix-specific Suppression of Integrin Activation in Shear Stress Signaling. Orr AW, Ginsberg MH, Shattil SJ, Deckmyn H, Schwartz MA. Mol Biol Cell. 2006 Aug 23; [Epub ahead of print]. Pubmed.
- The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis. Orr AW, Sanders JM, Bevard M, Coleman E, Sarembock IJ, Schwartz MA. J Cell Biol. 2005 Apr 11; 169(1):191-202. Pubmed.
- Trans-dominant inhibition of integrin function. Diaz-Gonzalez F, Forsyth J, Steiner B, Ginsberg MH. Mol Biol Cell. 1996 Dec; 7(12):1939-51. Pubmed.