GTP-Binding Proteins and Regulated Exocytosis

Abstract

Regulated exocytosis, which occurs in response to stimuli, is a two-step process involving the docking of secretory granules (SGs) at specific sites on the plasma membrane (PM), with subsequent fusion and release of granule contents. This process plays a crucial role in a number of tissues, including exocrine glands, chromaffin cells, platelets, and mast cells. Over the years, our understanding of the proteins involved in vesicular trafficking has increased dramatically. Evidence from genetic, biochemical, immunological, and functional assays supports a role for ras-like monomeric GTP-binding proteins (smgs) as well as heterotrimeric GTP-binding protein (G-protein) subunits in various steps of the vesicular trafficking pathway, including the transport of secretory vesicles to the PM. Data suggest that the function of GTP-binding proteins is likely related to their localization to specific cellular compartments. The presence of both G-proteins and smgs on secretory vesicles/granules implicates a role for these proteins in the final stages of exocytosis. Molecular mechanisms of exocytosis have been postulated, with the identification of a number of proteins that modify, regulate, and interact with GTP-binding proteins, and with the advent of approaches that assess the functional importance of GTP-binding proteins in downstream, exocytotic events. Further, insight into vesicle targeting and fusion has come from the characterization of a SNAP receptor (SNARE) complex composed of vesicle, PM, and soluble membrane trafficking components, and identification of a functional linkage between GTP-binding and SNARES.

Acidic Mammalian Chitinase Is Secreted via an ADAM17/Epidermal Growth Factor Receptor-dependent Pathway and Stimulates Chemokine Production by Pulmonary Epithelial Cells

“…ADAM17 transactivates EGFR on epithelial cells, which then in turn triggers a downstream signaling cascade involving Ras, thereby facilitating the trafficking and secretion of AMCase (11, 38 -40). The involvement of Ras in AMCase secretion is in accord with its known roles in exocytosis and vesicular trafficking (41,42). EGFR may also participate in the trafficking of intracellular AMCase, since EGFR is well known to be internalized and undergoes further endosomal processing and recycling (43)(44)(45).…”

Evidence that the small GTPase Rab8 is involved in melanosome traffic and dendrite extension in B16 melanoma cells

“…In many eukaryotic cells, the secretion of biomolecules is mediated through both the constitutive and regulated transport of vesicles (Pfeffer 1999). Accumulated evidence suggests that members of the Rab subfamily regulate vesiclemediated protein transport by recruiting tethering and docking factors to establish firm contact between the membranes to fuse, after which SNAREs become involved to complete the fusion process (Novick and Zerial 1997;Pfeffer 1999;Gerst 1999;Watson 1999). Each unique interorganelle transport pathway within the cell is regulated by a distinct Rab GTPase, and this is reflected in the localization of each Rab to distinct organelles (Seabra et al 2002;Novick and Zerial 1997;Lazar et al 1997).…”

Stabilities and Isomeric Equilibria in Solutions of Monomeric Metal-Ion Complexes of Guanosine 5′-Triphosphate (GTP4−) and Inosine 5′-Triphosphate (ITP4−) in Comparison with Those of Adenosine 5′-Triphosphate (ATP4−)

“…[1] Much recent activity centers on the so-called G-proteins, which utilize guanosine 5'-triphosphate (GTP 4À ) in such diverse processes as cellular signalling, protein synthesis, vesicular trafficking, and synaptic fusion. [2,3] G-proteins regulate ion channels, [4,5] affect the metabolism of Ca 2 , [5,6] and participate in signal transduction [7] and exocytosis, [8] etc. [3] Metal ions, mostly Mg 2 [5,9] but also Mn 2 [10] or Zn 2 , [11] are needed for the reactions.…”