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Filamin A: key actor in platelet biology.

J. Rosa,H. Raslova,M. Bryckaert

Published 2019 in Blood

ABSTRACT

Filamins (FLNs) are large dimeric actin binding proteins regulating actin cytoskeleton remodeling. In addition FLNs serve as scaffolds for signaling proteins such as tyrosine kinases, GTPases or phosphatases, as well as for adhesive receptors such as integrins. They thus connect adhesive receptors to signaling pathways and to cytoskeleton. There are 3 isoforms of FLNs (FLNa, FLNb, FLNc) originating from 3 homologous genes. FLNa has been the recent focus of attention because its mutations are responsible for a wide spectrum of defects, called filaminopathies A, affecting brain (peri-ventricular nodular heterotopia or PVNH), heart (valve defect), skeleton, gastro-intestinal tract or more recently, the megakaryocytic lineage. This review will focus on the physiological and pathological role of FLNa in platelets. Indeed, FLNa mutations alter platelet production from their bone marrow precursors, the megakaryocytes, yielding giant platelets in reduced number (macrothrombocytopenia). In platelet per se, FLNa mutations may either lead to impaired alphaIIbbeta3 integrin activation or in contrast, increased alphaIIbbeta3 activation, potentially enhancing the risk of thrombosis. Experimental work delineating the interaction of FLNa with its platelet partners, including alphaIIbbeta3, the von Willebrand receptor GPIb-IX-V, the tyrosine kinase Syk and the signaling pathway of the collagen receptor GPVI will also be reviewed.

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