Disease relevance of RAB11A

• In the esophageal adenocarcinoma resections, prominent Rab11 immunostaining was observed in the supranuclear region of low-grade dysplastic cells [1].
• We have sought to evaluate the expression of an important candidate regulator of apical trafficking, the small GTP-binding protein, Rab11, in resection and biopsy tissue from patients with Barrett's esophagus [1].
• Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin [2].
• Moreover, a dominant negative form of Rab11, which prevents exit of vesicular stomatitis virus glycoprotein from the Golgi complex, did not influence the capacity of GD3 to reach the cell surface [3].

High impact information on RAB11A

• The three GTPases Rab5, Rab4 and Rab11 regulate sequential transport steps along the endocytic/recycling pathway, and occupy distinct membrane domains on early and recycling endosomes [4].
• Localization of MT1-MMP within VSV-G/Rab8-positive vesicles, but not in Rab11/Tf/TfRc-positive compartment in invasive cells, suggests the involvement of the exocytic traffic pathway [5].
• Hence, we propose that FIP3 and FIP4 serve to couple Rab11-positive vesicle traffic from recycling endosomes to the cleavage furrow/midbody where they are tethered prior to fusion events via interactions with Arf6 and the Exocyst [6].
• The second was EEA-1 negative and with time recruited Rab11, suggesting that cytoplasts assembled functional REs [7].
• Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11 [8].

Biological context of RAB11A

• The RCP-Rab11 complex regulates endocytic protein sorting [9].
• RCP was therefore suggested to serve a dual function as Rab4 and Rab11 binding protein [9].
• In vitro binding of rab11 to native rab11BP requires partial denaturation of the latter to expose an internal binding site located between residues 334 and 504 that is apparently masked by the C-terminal portion of the protein, which includes six repeats known as WD40 domains [10].
• In cells overexpressing wild-type rab11, beta2ARs localized to a rab11-positive compartment and the rate of beta2AR recycling to the cell surface was reduced, but only after prolonged exposure to agonist and multiple rounds of receptor endocytosis and recycling [11].
• The YL8 gene could encode a guanine nucleotide binding protein of 216 amino acids with about 70% amino acid sequence identity to S. pombe YPT3, and is transcriptionally active in a variety of human cell lines [12].

Anatomical context of RAB11A

• We therefore propose that RCP functions primarily as a Rab11 binding protein that regulates protein sorting in tubular endosomes [9].
• The C2 domains of the class I Rab11 family of interacting proteins target recycling vesicles to the plasma membrane [13].
• Expression of Rab11-FIP4(C-ter) causes a dispersal of the Rab11 compartment towards the cell periphery and does not inhibit transferrin recycling in HeLa cells [14].
• Although rab11BP is primarily cytosolic, a significant fraction colocalizes with rab11 in endosomal membranes of both the sorting and recycling subcompartments [10].
• Both GTP-Rab11 and rabphilin-11 were colocalized at perinuclear regions, presumably the Golgi complex and recycling endosomes, in Madin-Darby canine kidney cells [15].

Associations of RAB11A with chemical compounds

• Treatment of HeLa cells with nocodazole caused disruption of microtubules and dispersion of GTP-Rab11 and rabphilin-11 [15].
• For the transferrin receptor, CXCR2, and the M4-muscarinic acetylcholine receptor, trafficking through the RE and receptor recycling is regulated by the small GTPase rab11 [11].
• Treatment with N-ethylmaleimide, the membrane transport inhibitor, caused an increased accumulation of syntaxin 4/rab11 positive vesicles in actin filament-like structures [16].
• One target of Rab11-mediated trafficking that contributes to invasion is the integrin alpha6beta4 [2].
• However, Rab11 overexpression inhibited cellular cholesterol esterification in an LDL-independent manner [17].

Physical interactions of RAB11A

• The Rab11 family of interacting proteins (Rab11-FIP) is a recently identified protein family composed of, to date, six members that interact with Rab11 [13].
• Rab11-FIP4 interacts with Rab11 in a GTP-dependent manner and its overexpression condenses the Rab11 positive compartment in HeLa cells [14].
• Myosin Vb interacts with Rab11 family members and is the major motor protein identified in association with plasma membrane recycling systems in nonpolarized and polarized cells [18].
• Molecular dissection of Rab11 binding from coiled-coil formation in the Rab11-FIP2 C-terminal domain [19].
• Expression of a rab11 mutant deficient in GTP binding (as a fusion between enhanced green fluorescent protein (EGFP) and the rab11S25N mutant) significantly slowed receptor recycling to the cell surface from dispersed transferrin-positive peripheral vesicles following a brief exposure to agonist [11].

Co-localisations of RAB11A

• In these vesicular structures syntaxin 4 colocalized with rab11, a marker of recycling endosomes [16].

Regulatory relationships of RAB11A

• These data highlight a pivotal role for rab11 in regulating the traffic of a G protein-coupled receptor at the level of the RE, where modulation of rab11 activity dictates the balance between receptor recycling and downregulation during prolonged exposure to agonist [11].
• Using a dominant negative approach, we determined that Rab11 regulates the recycling of CD44 from the vacuole but had no effect on major histocompatibility complex (MHC) class I recycling [20].
• Taken together, these data suggest that syntaxin 4 regulates secretion at the actin-rich areas of the plasma membrane and may be recycled through rab11 positive intracellular membranes [16].
• Rab11 in recycling endosomes regulates the sorting and basolateral transport of E-cadherin [21].
• The fact that the dominant negative (S25N) form of rab11 inhibits recycling of molecules interiorized at both temperatures indicates that activation of rab11 by GTP is required for exit of transferrin from sorting endosomes, regardless of whether this exit is toward the recycling compartment or directly to the plasma membrane [22].

Other interactions of RAB11A

• We have identified a novel 80-kDa protein that interacts specifically with the GTP-bound conformation of Rab4, and subsequent work has shown that it also interacts strongly with Rab11 [23].
• The isolated clone, corresponding to the carboxyl terminal 60 kDa of the myosin Vb tail, interacted with all members of the Rab11 family (Rab11a, Rab11b, and Rab25) [24].
• Rather, Gaf-1/Rip11 was capable of serving a link between gamma-SNAP and Rab11 [25].
• It colocalizes with early endosomal markers including Rab4 and Rab11 as well as with the transferrin receptor [23].
• Arfophilins are dual Arf/Rab 11 binding proteins that regulate recycling endosome distribution and are related to Drosophila nuclear fallout [26].

Analytical, diagnostic and therapeutic context of RAB11A

• In this study, we characterized interactions of FIPs with the Rab11 GTPase using isothermal titration calorimetric studies and mutational analysis [27].
• Here, we demonstrate with co-immunoprecipitation studies in HEK293 cells that there is a Rab11-TPbeta association occurring in the absence of agonist, which is not modulated by stimulation of TPbeta [28].
• Various constructs representing the C-terminal domain of Rab11-FIP2 were characterized by circular dichroism, and their affinity with Rab11 was measured using isothermal titration calorimetry [19].
• Utilising a polyclonal antibody specific for Rab11-FIP3, we have demonstrated by immunofluorescence microscopy that Rab11-FIP3 colocalises with Rab11 in a distinctive pericentrosomal location in A431 cells [29].
• The sequence analysis of 24KG revealed that a 24KG cDNA is the rat counterpart of a rab11 cDNA cloned from a Madin-Darby canine kidney cell cDNA library [30].

References