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.

Keywords: Endocytosis; GTPase; exocytosis; platelets; trafficking.

Figure 1.

Membrane trafficking events within megakaryocytes and platelets involving Rab, Arf and Ras GTPases. (A) Granule biogenesis within the megakaryocyte involves input from biosynthetic and (B) endocytic pathways culminating in cargo packaging into early endosomes before sorting in immature multi-vesicular bodies (MVB I) to mature MVB II/late endosomes, or targeting to recycling endosomes. Following biogenesis, α-granules (AG), lysosomes (LY) and dense granules (DG) mature within platelets before targeting to the plasma membrane for (C) exocytosis. Trafficking roles for GTPases studied in megakaryocytes/platelets are highlighted in green, while roles for GTPases inferred from other cell systems are highlighted in red.

Figure 2.

Ranked protein expression of 42 Rab GTPases in human platelets as detected in the Burkhart platelet proteome screen [28].

Figure 3.

Ranked protein expression of 14 Arf GTPases and 12 Ras GTPases in human platelets as detected in the Burkhart platelet proteome screen [28].