Review
Orchestration of cell surface proteins by Rab11

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Highlights

  • The vesicle transport protein Rab11 has diverse cellular functions and its dysregulation is linked to cancer.

  • Rab11 proteins form complexes with myosin, kinesin, and dynein motor proteins.

  • The GTP/GDP status of Rab11 allows for distinct protein complex formation.

  • TBC and DENN family proteins regulate the Rab11 GTP/GDP cycle.

The organization of cells into interconnected structures such as animal tissues requires a sophisticated system directing receptors and adhesion proteins to the cell surface. The Rab11 small G proteins (Rab11a, b, and Rab25) of the Ras superfamily are master regulators of the surface expression of receptors and adhesion proteins. Acting as a molecular switch, Rab11 builds distinct molecular machinery such as motor protein complexes and the exocyst to transport proteins to the cell surface. Recent evidence reveals Rab11 localization at the trans-Golgi network (TGN), post-Golgi vesicles, and the recycling endosome, placing it at the intersection between the endocytic and exocytic trafficking pathways. We review Rab11 in various cellular contexts, and discuss its regulation and mechanisms by which Rab11 couples with effector proteins.

Section snippets

Cytoskeletal transport tracks

Just as traffic routes and logistic centers are a necessity for daily life, the structuring and communication of cellular networks strongly depends on transport processes. Analogous to the macroscopic world, our cellular microcosm has fast track routes for long-distance transport, and slower but more flexible transport systems for the delivery of cargo to outlying areas. Microtubule tracks and associated motor proteins enable high velocity and long-distance transport, whereas transport by the

Mammalian Rab11 proteins

The mammalian genome encodes three Rab11 proteins, Rab11a, b, and c, which share high sequence identity (mouse proteins, Rab11a: Rab11b, 91% identity; Rab11a: Rab11c, 62% identity; Rab11b: Rab11c, 61% identity). Rab11c is better known as Rab25 and is termed thus henceforth in this paper. Tissue expression of mammalian Rab11 proteins is variable. Whereas Rab11a has a ubiquitous expression pattern [5], gene expression studies have shown a restricted expression of Rab11b (brain, testis, and heart)

Rab11-regulated transport processes

Rab11 proteins have been implicated in a variety of cellular traffic pathways. They localize to the TGN and post-Golgi vesicles of the secretory pathway [9], as well as control traffic through the pericentriolar recycling endosome. Indeed, studies have shown that overexpression of an interfering Rab11 mutant does not influence early steps of cellular uptake and recycling of transferrin, but does inhibit recycling from the later recycling endosome [10]. Studies of Rab11 function in epithelial

Rab11 motor protein complexes

Important insight into the molecular mechanisms of how a single small G protein can act in various cell biological processes was gained through the discovery of Rab11 in multiple motor protein complexes. By interacting with adaptor proteins, Rab11 can form complexes with distinct motor proteins, which enable bidirectional transport along microtubule tracks, as well as actin-filament-dependent transport. The varying motor proteins guide Rab11 vesicles to varying subcellular locales of different

GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) regulating the Rab11–GDP/GTP cycle

It is a well-accepted principle that the GTP/GDP status determines the interaction of Ras superfamily proteins with effector proteins. The GTP/GDP cycle is regulated by GAPs, which catalyze the hydrolysis of GTP into GDP, and GEFs, which mediate the exchange from GDP to GTP [2]. The GAPs and GEFs therefore control the cellular functions of small G proteins.

Rab11 and human disease

The best-studied role of the Rab11 protein in human disease is the involvement of Rab25 (Rab11c) in cancer. Rab25 has been identified as an oncogene that is overexpressed in ovarian and breast cancers [62], and as a tumor-suppressor gene in colon cancer [63]. Increased Rab25 mRNA levels associate with a marked decrease in survival rate of patients with ovarian and breast cancers. Forced expression of Rab25 in cell culture experiments increases anchorage-dependent and anchorage-independent cell

Concluding remarks

Because of its numerous cell biological functions, as well as the diversity of protein complexes with which it is involved, studying Rab11 function remains a fascinating and likely rewarding undertaking for future studies. The identification of regulation and integration of the different Rab11 functions into cellular signal transduction cascades will be an especially important objective. Rab11 interacts with different effectors depending on its GTP/GDP status. It has been a dogmatic belief in

Acknowledgments

The work was supported by the Bavarian Genome Research Network (BayGene) and the German Research Foundation (DFG, priority programme SPP 1464).

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