Kalirin/Trio Rho Guanine Nucleotide Exchange Factors Regulate a Novel Step in Secretory Granule Maturation

Abstract

The molecular mechanisms involved in the maturation of secretory granules, organelles that store hormones and neuropeptides, are poorly understood. As granule content proteins are processed, the composition of granule membranes changes, yielding constitutive-like secretion of immature content proteins and producing secretagogue-responsive mature granules. Constitutive-like secretion was not previously recognized as a process subject to regulation. We show that Kalirin and Trio, homologous Rho guanine nucleotide exchange factors (GEFs), which interact with a secretory granule resident protein, modulate cargo secretion from immature granules. Some of the Kalirin and Trio isoforms expressed in neuroendocrine cells colocalize with immature granules. Overexpression of their N-terminal GEF domain (GEF1) enhances secretion from immature granules, depleting cells of secretory cargo in the absence of secretagogue. This response requires GEF1 activity and is mimicked by Kalirin/Trio substrates Rac1 and RhoG. Accordingly, selective pharmacological inhibition of endogenous GEF1 activity decreases secretagogue-independent release of hormone precursors, accumulating product peptide in mature secretory granules. Kalirin/Trio modulation of cargo secretion from immature granules provides secretory cells with an extra layer of control over the sets of peptides released. Control of this step enhances the range of physiological responses that can be elicited, whereas lack of control could have pathological consequences.

βPIX-activated Rac1 stimulates the activation of phospholipase D, which is associated with exocytosis in neuroendocrine cells

“…secretion (Ferraro et al, 2007), whereas intersectin 1L, a GEF for Cdc42 activates the exocytotic machinery in PC12 cells (Malacombe et al, 2006). Additionally, βPix, an exchange factor for Rac1 has been described to be recruited by Scrib at the plasma membrane during exocytosis (Audebert et al, 2004).…”

UNC-73/Trio RhoGEF-2 Activity Modulates Caenorhabditis elegans Motility Through Changes in Neurotransmitter Signaling Upstream of the GSA-1/Gαs Pathway

“…Kalirin was originally identified through its association with peptidylglycineamidating monooxygenase (PAM), a neuropeptide processing enzyme that functions in DCVs (Alam et al 1997;Mains et al 1999). Kalirin and Trio modulate DCV maturation in pituitary derived AtT-20 neuroendocrine cells and their isoforms are differentially associated with Golgi, immature DCVs, and endosomes (Ferraro et al 2007). Increasing Kalirin or Trio activity depletes immature DCVs of their hormone cargo, while Kalirin or Trio inhibition increases the amount of mature hormone product in mature DCVs.…”

Distinct Linkage between Post-translational Processing and Differential Secretion of Progastrin Derivatives in Endocrine Cells

“…It might be another example of a value of differentiated secretion of progastrin-processing products. It was recently shown that the Rho homologous guanine exchange factors, Kalirin and Trio, can modulate secretion response of the constitutive-like vesicles and the mature granules (39). Thus, secretion of glycine-extended gastrins over gastrins might be subjected to specific regulation.…”