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Pleckstrin
Pleckstrins are a family of proteins found in platelets[1] and other cells. The name derives from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. The prototype protein, now called pleckstrin-1, was first identified in 1979 as the major substrate of protein kinase C in platelets.[2] The homolog pleckstrin-2 is more widely expressed in tissues.[3] The pleckstrin homology domain (PH domain) was named after pleckstrin-1.[2] Sequence and structureBoth pleckstrin-1 and pleckstrin-2 contain two pleckstrin homology domains, separated by a central dishevelled-Egl10-pleckstrin (DEP) domain. Pleckstrin-1 is phosphorylated by protein kinase C on three serine and threonine residues located between the first pleckstrin homology domain and the DEP domain;[2] pleckstrin-2 is not a substrate for protein kinase C.[2][4] The two proteins share 65% sequence homology[2] and have a size of about 47 kilodaltons.[5] As of 2024, no high-resolution three-dimensional structure has been solved for full-length pleckstrin, but the structures of the individual domains of both pleckstrin-1 and -2 have been published.[2] FunctionsPleckstrins are involved in rearranging the actin cytoskeleton in such processes as platelet activation, erythropoeisis, and cell spreading by extension of filopodia and lamellipodia.[3] Pleckstrin-1 is believed to become activated by protein kinase C phosphorylation, which results in binding of the membrane lipid phosphatidylinositol 3,4-bisphosphate.[2] Interactions with integrins and the Rac GTPase then lead to reorganization of the actin cytoskeleton.[3] Pleckstrin-2 also binds to inositol phospholipids, but interacts directly with F-actin, unlike pleckstrin-1.[3] Since pleckstrin-2 is expressed in a wider variety of cell types, its biological roles are more diverse than those of pleckstrin-1. Pleckstrin-1 is a key protein in the membrane remodelling processes that occur during platelet activation.[2] It also occurs in immune cells such as macrophages and neutrophils,[2][3] where it is involved in formation of phagosomes and the secretion of proinflammatory cytokines.[3] Pleckstrin-2 has roles in cell spreading, inflammation, erythropoeisis, and tumorigenesis. In lymphocytes, it is involved in PI3 kinase-mediated immune synapse formation. Pleckstrin-2 also mediates cytoskeletal changes involved in proliferation of erythroblasts early in erythropoeisis. It is also believed to be crucial in the epithelial-to-mesenchymal transition in tumor metastasis, and pleckstrin-2 is known to be overexpressed in a variety of cancers.[3] References
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