Analysis of Rab18 and a New Golgin in the Secretory Pathway

Malagón, Marı́a M.; Cruz, Daniel Filipe; Vázquez-Martı́nez, Rafael; Peinado, Juan R.; Anouar, Youssef; Tonon, Marie‐Christine; Vaudry, Hubert; Gracia‐Navarro, Francisco; Castaño, Justo P.

doi:10.1196/annals.1327.017

Cited by 8 publications

(7 citation statements)

References 6 publications

(8 reference statements)

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“…storage melanotropes) presented higher Rab18 mRNA levels than those melanotropes displaying hypersecretory phenotype (i.e. secretory melanotropes) (19,20). In the present work, we have investigated Rab18 protein in these melanotrope subpopulations.…”

Section: Resultsmentioning

confidence: 94%

“…displaying high amount of a-MSH containing secretory granules but low secretory activity, both under basal conditions and in response to stimulatory factors) than in melanotrope cells displaying a secretory phenotype (i.e. with low intracellular a-MSH content but high basal secretory activity, and a strong secretory response to stimulatory secretagogues) (19,20). In the present work, we have furthered our study on the expression and subcellular localization of Rab18 in both endocrine and neuroendocrine cell types, and investigated its role in relation to the regulated secretory pathway.…”

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confidence: 99%

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Rab18 Inhibits Secretory Activity in Neuroendocrine Cells by Interacting with Secretory Granules

Vázquez-Martı́nez

Cruz-García

Durán-Prado

et al. 2007

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Rab proteins comprise a complex family of small GTPases involved in the regulation of intracellular membrane trafficking and reorganization. In this study, we identified Rab18 as a new inhibitory player of the secretory pathway in neuroendocrine cells. In adrenal chromaffin PC12 cells and pituitary AtT20 cells, Rab18 is located at the cytosol but associates with a subpopulation of secretory granules after stimulation of the regulated secretory pathway, strongly suggesting that induction of secretion provokes Rab18 activation and recruitment to these organelles. In support of this, a dominant‐inactive Rab18 mutant was found to distribute diffusely in the cytosol, whereas a dominant‐active Rab18 mutant was predominantly associated to secretory granules. Furthermore, interaction of Rab18 with secretory granules was associated to an inhibition in the secretory activity of PC12 and AtT20 cells in response to stimulatory challenges. Association of Rab18 with secretory granules was also observed by immunoelectron microscopy in normal, non‐tumoral endocrine cells (pituitary melanotropes), wherein Rab18 protein content is inversely correlated to the level of secretory activity of cells. Taken together, these findings suggest that, in neuroendocrine cells, Rab18 acts as a negative regulator of secretory activity, likely by impairing secretory granule transport.

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Section: Resultsmentioning

confidence: 94%

mentioning

confidence: 99%

Rab18 Inhibits Secretory Activity in Neuroendocrine Cells by Interacting with Secretory Granules

Vázquez-Martı́nez

Cruz-García

Durán-Prado

et al. 2007

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“…Rab18 has been localized to endosomes of mammalian cells by antibody staining in previous studies (Lutcke et al, 1994;Yu et al, 1993) and more recently to lipid droplets by multiple techniques including mass spectrometric analysis of purified lipid droplets (Brasaemle et al, 2004;Liu et al, 2004;Umlauf et al, 2004), immunofluorescence (Martin et al, 2005;Ozeki et al, 2005) and immunoelectron microscopy (Martin et al, 2005;Ozeki et al, 2005). Previous to this study, no fundamental generalized role has been proposed for Rab18 in the secretory pathway, although evidence has been provided for a role as a negative regulator of secretion in neuroendocrine cells (Malagon et al, 2005;Vazquez-Martinez et al, 2007).…”

Section: Role Of Rab18 In Golgi To Er Transportmentioning

confidence: 95%

Rab18 and Rab43 have key roles in ER-Golgi trafficking

Dejgaard

Murshid

Erman

et al. 2008

Journal of Cell Science

155

141

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Rabs and Arfs/Arls are Ras-related small GTPases of particular relevance to membrane trafficking. It is thought that these proteins regulate specific pathways through interactions with coat, motor, tether and SNARE proteins. We screened a comprehensive list of Arf/Arl/Rab proteins, previously identified on purified Golgi membranes by a proteomics approach (37 in total), for Golgi or intra-Golgi localization, dominant-negative and overexpression phenotypes. Further analysis of two of these proteins, Rab18 and Rab43, strongly indicated roles in ER-Golgi trafficking. Rab43-T32N redistributed Golgi elements to ER exit sites without blocking trafficking of the secretory marker VSVG-GFP from ER to cell surface. Wild-type Rab43 redistributes the p150Glued subunit of dynactin, consistent with a specific role in regulating association of pre-Golgi intermediates with microtubules. Overexpression of wild-type GFP-Rab18 or incubation with any of three siRNAs directed against Rab18 severely disrupts the Golgi complex and reduces secretion of VSVG. Rab18 mutants specifically enhance retrograde Golgi-ER transport of the COPI-independent cargo β-1,4-galactosyltransferase (Galtase)-YFP but not the COPI-dependent cargo p58-YFP from the Golgi to ER in a photobleach assay. Rab18-S22N also potentiated brefeldin-A-induced ER-Golgi fusion. This study is the first comprehensive application of large-scale proteomics to the cell biology of small GTPases of the secretory pathway.

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“…In relation to the participation of Rab18 in the secretory pathway, a differential display analysis of genes expressed in pituitary melanotropes enabled us to isolate the RAB18 gene by virtue of its preferential expression in a subset of cells exhibiting low hormone secretory activity (Malagon et al, 2005). Further subcellular localization studies of Rab18 in (neuro)endocrine cells lines, such as the rat pheochromocytoma PC12 cell line, the adrenocorticotropin (ACTH)-secreting AtT20 cell line, and α-melanotropin stimulating hormone-producing melanotrope cells showed that this GTPase mainly distributed diffuse in the cytosol under non-stimulated conditions, whereas after specific stimulation of the cell secretory activity it colocalized with the secretory granule markers secretogranin II, chromogranin A, and NPY.…”

Section: Protein Structure Subcellular Localization and Function Of mentioning

confidence: 99%

Rab Proteins and the Secretory Pathway: The Case of Rab18 in Neuroendocrine Cells

Vázquez-Martı́nez¹,

Malagón²

2011

Front. Endocrin.

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The secretory pathway is a process characteristic of cells specialized in secretion such as endocrine cells and neurons. It consists of different stages that are dependent on specific transport of proteins in vesicular-tubular carriers. Biochemical analyses have unveiled a number of protein families that confer identity to carrier vesicles and specificity to their transport. Among them is the family of Rab proteins, Ras-like small GTPases that anchor to the surface of transport vesicles and participate in vesicle formation from the donor compartment, transport along cytoskeletal tracks, and docking and fusion with the acceptor compartment. All of these functions are accomplished through the recruitment of effector proteins, such as sorting adaptors, tethering factors, kinases, phosphatases, and motors. The numerous Rab proteins have distinct subcellular distributions throughout the endomembrane system, which ensures efficient cargo transfer. Rab proteins act as molecular switches that alternate between a cytosolic GDP-bound, inactive form and a membrane-associated GTP-bound, active conformation. Cycling between inactive and active states is a highly regulated process that enables Rabs to confer spatio-temporal precision to the different stages through which a vesicle passes during its lifespan. This review focuses on our current knowledge on Rab functioning, from their structural features to the multiple regulatory proteins and effectors that control Rab activity and translate Rab function. Furthermore, we also summarize the information available on a particular Rab protein, Rab18, which has been linked to the control of secretory granule traffic in neuroendocrine cells.

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Analysis of Rab18 and a New Golgin in the Secretory Pathway

Cited by 8 publications

References 6 publications

Rab18 Inhibits Secretory Activity in Neuroendocrine Cells by Interacting with Secretory Granules

Rab18 Inhibits Secretory Activity in Neuroendocrine Cells by Interacting with Secretory Granules

Rab18 and Rab43 have key roles in ER-Golgi trafficking

Rab Proteins and the Secretory Pathway: The Case of Rab18 in Neuroendocrine Cells

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