Transmembrane signaling across the platelet integrin glycoprotein IIb-IIIa.
The platelet membrane is lined by a membrane skeleton, which in turn appears to be associated with underlying cytoplasmic actin filaments. Glycoprotein IIb-IIIa appears to associate with the membrane skeleton in unstimulated platelets. Upon platelet activation, unidentified intracellular signals cause GP IIb-IIIa to become competent to bind adhesive ligand. We suggest that the membrane skeleton may play a role in allowing this inside-out signaling. Signaling molecules that appear to associate with the membrane skeleton in unstimulated platelets include pp60c-src, pp62c-yes, and GAP. Preliminary evidence suggests that components of the membrane skeleton may become phosphorylated on tyrosine residues prior to GP IIb-IIIa-ligand interactions. Once GP IIb-IIIa binds adhesive ligand in a platelet aggregate, there is signaling in the opposite direction. One consequence of the outside-in transmembrane signaling is that the membrane skeleton becomes more tightly associated with the underlying actin filaments as focal contact-like structures form. Proteins that accumulate in these focal contact-like structures with a time course identical to that of GP IIb-IIIa and in a GP IIb-IIIa-dependent manner include talin, vinculin, and spectrin. Signaling molecules that accumulate in the focal contact-like structures include pp60c-src, pp62c-yes, phosphoinositide 3-kinase, and protein kinase C. These are potential candidates for the enzymes that mediate the ligand-induced transmembrane signaling. Another enzyme involved in the ligand-induced signaling is calpain. This enzyme is activated as a consequence of ligand-GP IIb-IIIa interactions and cleaves components of the membrane skeleton. Future experiments will be needed to identify other signaling enzymes activated as a consequence of GP IIb-IIIa interactions and to determine which ones are responsible for inducing the cytoskeletal reorganizations that occur in platelets and other cells when integrins bind their adhesive ligands.
Children's Hospital Oakland Research Institute, California 94609.
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JE
Fox
D000818:Animals; D001792:Blood Platelets / Q000502:physiology* / Q000648:ultrastructure; D002462:Cell Membrane / Q000502:physiology* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000502:physiology; D006801:Humans; D008961:Models, Structural; D010973:Platelet Adhesiveness; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*
D010980:Platelet Membrane Glycoproteins; D013917:Thrombin