Platelet signal transduction: Focal Adhesion Kinases

Platelets are highly reactive cells in the circulation, primarily responsible for hemostasis and thrombosis. Their activation is initiated by various extracellular stimuli that induce morphological changes, cell spreading, granule secretion, aggregation, and clot retraction. Platelets possess an extensive array of membrane receptors that collect and integrate signals from soluble agonists, adhesive proteins, and mechanical forces, thereby triggering platelet activation, predominantly through G-protein-coupled signaling pathways and tyrosine kinase-mediated phosphorylation cascades.

Platelets express a substantial number of non-receptor tyrosine kinases, which participate in platelet activation via distinct mechanisms that generally respect defined hierarchical patterns. Src family kinases (SFKs) constitute the initial tier of signaling molecules, as they are generally directly activated by membrane receptors and mediate the early events in platelet activation. The second tier of protein tyrosine kinases includes enzymes that are not directly activated by membrane receptors but are positioned downstream of SFKs. This group includes the focal adhesion kinases FAK and Pyk2.

Focal adhesion kinases were initially identified as key components of focal adhesions in adherent cells, associated with cytoskeletal elements and integrins. More than three decades ago, focal adhesion kinases were identified in blood platelets, and substantial information regarding their structure and activation mechanisms was established during the early twenty-first century. However, more recent advancements in the development of specific inhibitors and the generation of full or conditional knockout mice have provided deeper insights into their specific roles in platelet physiology, revealing the unique and non-redundant functions of FAK and Pyk2.