Small GTPases in platelet membrane trafficking

Abstract

Our understanding of fundamental biological processes within platelets is continually evolving. A critical feature of platelet biology relates to the intricate uptake, packaging and release of bioactive cargo from storage vesicles, essential in mediating a range of classical (haemostasis/thrombosis) and non-classical (regeneration/inflammation/metastasis) roles platelets assume. Pivotal to the molecular control of these vesicle trafficking events are the small GTPases of the Ras superfamily, which function as spatially distinct, molecular switches controlling essential cellular processes. Herein, we specifically focus on members of the Rab, Arf and Ras subfamilies, which comprise over 130 members and platelet proteomic datasets suggest that more than half of these are expressed in human platelets. We provide an update of current literature relating to trafficking roles for these GTPases in platelets, particularly regarding endocytic and exocytic events, but also vesicle biogenesis and provide speculative argument for roles that other related GTPases and regulatory proteins may adopt in platelets. Advances in our understanding of small GTPase function in the anucleate platelet has been hampered by the lack of specific molecular tools, but it is anticipated that this will be greatly accelerated in the years ahead and will be crucial to the identification of novel therapeutic targets controlling different platelet processes.

Calpain cleaves phospholipid flippase ATP8A1 during apoptosis in platelets

“…61,62 Given the absence of ATP8A1 in the 226 JING et al plasma membrane of platelets (Figure 1D), we reason that ATP8A1 is predominantly located in intracellular membranes and is involved in vesicle-mediated trafficking in platelets. Platelets have complete intracellular membrane systems 63 and possess fundamental membrane trafficking processes such as endocytosis. 64 Moreover, upon activation, platelets undergo dramatic shape change 1 and carry out exocytosis such as secretion of procoagulant components and release of granules (dense-/a-granule).…”

Small Rab GTPases in Intracellular Vesicle Trafficking: The Case of Rab3A/Raphillin-3A Complex in the Kidney

“…In myocytes, Rab9-dependent autophagosomes recognize and engulf damaged mitochondria, resulting in ischemia-reperfusion (IR) changes in oxidative phosphorylation, eventually decreasing cardiomyocyte viability [ 35 , 36 , 37 ]. In diabetic patients with albuminuria, a genome-wide association study identified a genetic locus of Rab38 associated with albuminuria, highlighting novel pathways influencing albuminuria [ 38 ].…”

Defective RAB31-mediated megakaryocytic early endosomal trafficking of VWF, EGFR, and M6PR inRUNX1deficiency

“…More than 70 members of the Rab family have been identified, and they play specific roles in vesicle trafficking, depending on their cellular locations. 1,2,4 At least 40 Rab proteins are recognized in human platelets, 4 but specific roles in vesicle trafficking are unknown in platelets or megakaryocytes for the majority. RAB31 (Ras-related protein in brain 31), a member of the RAB5 subfamily of Rab GTPases, was cloned from human platelets, 5 and it shared 82% homology with RAB22B protein identified in human melanocytes.…”