Platelet Integrin Activation Pathway Described

A recently published paper has traced the molecular pathway for activation of the integrin GPIIb-IIIa in blood platelets.

Integrins are integral membrane proteins that are exposed to both the cell cytoplasm and to the extracellular environment (extracellular matrix, ECM). Connections between integrin and the ligands in ECM and the microfilaments inside the cell are indirect: they are linked via scaffolding proteins such as talin, paxillin, and alpha-actinin. These proteins act by regulating kinases such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as Crk. Cell attachment to the ECM is a basic requirement for building multicellular organisms. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings.

Investigators at the University of California, San Diego (USA), focused on the GPIIb-IIIa integrin from blood platelets. Mutations in the gene for this integrin have been linked to formation of blood clots and development of cardiovascular disease. The investigators used forward, reverse, and synthetic genetics to engineer and order an activation pathway for the integrin.

They reported in the September 19, 2006, online edition of Current Biology that talin binding seemed to be responsible for activation of the pathway. Addition of controllable amounts of talin and the enzyme protein kinase C to platelet cultures caused the cells to respond to certain agents that, in turn, activated platelet integrin GPIIb-IIIa.

"Drugs such as aspirin and clopidogrel work in large part by blocking the activation of GPIIb-IIIa. These drugs do not work directly on GPIIb-IIIa, but do block signaling pathways that indirectly contribute to GPIIb-IIIa activation. Thus, they achieve a chronic anti-thrombotic effect with acceptable risk of bleeding,” explained senior author Dr. Mark H. Ginsberg, professor of medicine at the University of California, San Diego. "The road map of the activation pathway could lead to the development of new antithrombotic drugs or treatments for inflammatory diseases. In addition, the ability to engineer these activation pathways may contribute to efforts to develop artificial platelets or leukocytes that could be used in patients with suppressed bone marrow function.”



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