Collagen-mediated platelet activation and PI3K

Phosphatidylinositol 3–kinase (PI3K) is a phospholipid kinase that is involved in diverse cellular events, including the prevention of apoptosis, regulation of glucose metabolism, chemotaxis, and cell proliferation. It is far from obvious what role this enzyme would play in a platelet—a terminally differentiated anucleate cell. Studies using less-than-specific pharmacologic inhibitors have a suggested that PI3K might participate in both collagen-induced platelet activation and the irreversible phase of platelet aggregation (Kovacsovics et al, J Biol Chem. 1995;270:11358-11366; Pasquet et al, Biochem J. 1999;342(pt 1): 171-177).

Most cells have multiple isoforms of PI3K that are composed of a regulatory subunit and a catalytic subunit. Using cells obtained from genetically modified mice, investigators have begun to understand the role of different PI3K isoforms in hematopoietic cells. For example, mice lacking the p110γ catalytic subunit of PI3K have a defect in ADP-mediated platelet aggregation (Hirsch et al, FASEB J. 2001;15:2019-2021), while mice lacking the p85α regulatory subunit of PI3K have impaired B-cell development. In this issue, Watanabe and colleagues (page 541) have studied the effects of the p85α knockout on platelet function. They found that in the absence of p85α there was a defect in signaling events initiated by the platelet collagen receptor, GPVI, whereas there was no defect in platelet activation following stimulation by other platelet agonists such as ADP or thrombin.

It is noteworthy that GPVI signaling pathways are similar to those emanating from the B-cell antigen receptor, as well as other members of the immunoglobulin supergene family of receptors. Does the work by Watanabe et al suggest that therapeutic targeting of p85α would be a useful way to disrupt platelet activation following exposure to subendothelial collagen such as occurs during coronary plaque rupture? Given the ubiquitous expression and diverse functions of PI3K, such speculation is premature.