Small GTPases in platelet membrane trafficking

Figures & data

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].

Table I. Summary of small GTPases discussed in this review. Mouse models are described, unless otherwise stated. Studies using pharmacological inhibitors or permeabilised platelet systems are not included.

		Effect on granule count/content/secretion
Protein	Gene	Alpha	Dense	Lysosome	Model	Reference
Rab27A	RAB27A	Normal vWF levels, normal P-selectin exposure	Normal count/5HT content	nd	Ashen mouse (Rab27a^−/- global)	Barral et al. (2002)
Rab27B	RAB27B	Normal P-selectin exposure	Reduced count/5HT content, secretion defect-further impaired in Rab27a/b null	nd	Rab27b^−/- (global)	Tolmachova et al. (2007)
Rab38	RAB38	Normal count, and P-selectin exposure	None detected in Megs or Platelets	Normal count	FHH rat (Rab38^−/- due to point mutation in gene ATG start site)	Ninkovic et al. (2008)
Rab32	RAB32	nd	Biogenesis defect in Megs	nd	Rab32 siRNA (MEG-01 cells)	Ambrosio et al. (2012)
Rab38	RAB38	nd	Biogenesis defect in Megs	nd	Rab38 siRNA (MEG-01 cells)	Ambrosio et al. (2012)
Arf6	ARF6	Normal count, decreased fibrinogen content	Normal count and secretion	nd	Arf6^flox/flox- PF4-Cre	Huang et al. (2016)
RalA	RALA	Normal count, and secretion*	Normal count and secretion†	Normal count and secretion	RalA ^flox/flox-PF4-Cre	Wersäll et al. (2018)
RalB	RALB	Normal count, P-selectin exposure defect*	Normal count and secretion†	Normal count and secretion	RalB^flox/flox- PF4-Cre	Wersäll et al. (2018)
R-Ras2	RRAS2	GPVI-specific secretion defect	GPVI-specific secretion defect	nd	Rras2^−/- (global)	Janapati et al. (2018)

‘*’ P-selectin exposure defect markedly enhanced and ‘†’ mild ATP secretion defect in RalA/B double knockout platelets, ‘nd’ indicates no data available, ‘FHH’ indicates fawn-hooded hypertensive.

Burkhart JM, Vaudel M, Gambaryan S, Radau S, Walter U, Martens L, Geiger J, Sickmann A, Zahedi RP. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood 2012;120:e73–82. doi:10.1182/blood-2012-04-416594

 PubMed Web of Science ®Google Scholar