Multiple aspects of Rab protein action in the secretory pathway: Focus on Rab3 and Rab6
Introduction
More than 30 proteins (including isoforms) comprise the Rab/Ypt family of GTP-binding proteins. These proteins regulate discrete transport steps along the secretory and endocytic pathways. So far, it has not been possible to delineate precisely the function of Rab proteins. They were first described as proof-reading devices implicated in the specificity of vesicle targeting [1]. More recently, evidence was obtained that Rab proteins might serve as tethering factors between transport vesicles and the acceptor membrane [2]. Furthermore, a link between molecular motors and Rabs has been elucidated. In fact, the list of putative effectors of Rabs is continuously growing and, accordingly, the general picture becomes complex. We will focus here on two members of the Rab family, Rab3 and Rab6, which are implicated in regulated exocytosis of hormones and neurotransmitters and in membrane trafficking at the Golgi level, respectively. For general information on the Rab family of GTP-binding proteins, the reader could benefit from a number of recent reviews devoted to the localization of the Rab proteins, to the Rab cycle and to their mechanism of action [2], [3], [4], [5]. Our aim is to illustrate the functional diversity of Rab proteins, and to give some clues towards its understanding.
Section snippets
RAB3
Many Rab proteins are ubiquitous. In contrast, Rab3 is enriched in neurons and endocrine cells. In agreement with this specific pattern of expression, the four proteins (Rab3 A–D) that comprise the Rab3 subfamily are implicated in a specific trafficking pathway, apart from the constitutive endocytic and exocytic routes. Physically, Rab3 proteins are associated with secretory vesicles [6], [7], [8], [9], [10], [11], [12], [13], [14]. Functionally, most of the studies point towards a role for
RAB6
There was until now some confusion about the exact function of Rab6, and several (at least at first appearance) contradictory results have been reported. Especially, the relatively wide distribution of Rab6 has led to speculation that there may be several roles for this protein. The recent demonstration that three Rab6 isoforms (termed Rab6A, A’/C and B) exist in mammals, allows a clarification of this issue. In addition, a role for Rab6A in a new Golgi to endoplasmic reticulum (ER) route has
Conclusion
Given all of their regulatory functions, it is now safe to say that Rabs are truly master regulators of membrane trafficking and organelle localisation in mammalian cells. The necessary complexity comes from the specific interaction of a given Rab or its isoform, with a subset of effectors. Not only the Rab isoforms, but also their effectors, can be expressed in different cell types and by such combinations Rabs exert their pivotal role.
Acknowledgements
We thank Drs. G. Langsley and B. Poulain for critical reading of the manuscript.
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