Disease relevance of RAB5A

• To study the effect of RAB5A gene on microfilaments in human lung adenocarcinoma cells, AGZY83-a cells were stained with fluorescein isothiocyanate (FITC)-phalloidin [1].
• The result may be a powerful experimental evidence that over-expression of RAB5A gene associated with neoplasia metastasis [2].
• Using immunohistochemical staining, we also examined RAB5A change at protein level in 45 cases human non-small cell lung carcinoma paraffin sections [2].
• Probably, over-expression of RAB5A gene in non-small lung cancer may serve as a diagnostic marker for metastasis [3].
• In marked contrast, in PU.1(Pos) mAM(PU.1+) and MH-S cells, adenovirus failed to escape from endosomes, colocalized exclusively with endosome/lysosome markers (Rab5, Rab7, and Lamp1), and rarely expressed the reporter [4].

High impact information on RAB5A

• Here, we report that Rabex-5, a guanine nucleotide exchange factor for Rab5, binds to Ub through two independent UBDs [5].
• We found a kinesin-3, KIF16B, that transports early endosomes to the plus end of microtubules in a process regulated by the small GTPase Rab5 and its effector, the phosphatidylinositol-3-OH kinase hVPS34 [6].
• APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment [7].
• This pathway operates via APPL1 and APPL2, two Rab5 effectors, which reside on a subpopulation of endosomes [7].
• Our findings identify an endosomal compartment bearing Rab5 and APPL proteins as an intermediate in signaling between the plasma membrane and the nucleus [7].

Chemical compound and disease context of RAB5A

• The D136N mutant of Rab5, which was predicted to switch specificity from guanine to xanthine nucleotides, was expressed in E. coli, extracted with urea, purified by column chromatography, and refolded by stepwise dialysis against buffer containing XDP [8].

Biological context of RAB5A

• We report the identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogenesis [7].
• The binding site for gamma(1)-adaptin is in the hinge region of rabaptin-5alpha, which is distinct from rab4- and rab5-binding domains [9].
• Overexpression of RN-tre blocks the internalization of both proteins, consistent with its function as a negative regulator of Rab5 and endocytosis [10].
• SARA, a FYVE domain protein, affects Rab5-mediated endocytosis [11].
• Similar to RN-Tre, we found that PRC17 protein interacts directly with Rab5 and stimulates its GTP hydrolysis [12].

Anatomical context of RAB5A

• TBC1D3 is a member of the TBC1 domain family of proteins that stimulates the intrinsic GTPase activity of RAB5A, an essential actor in early endosome trafficking [13].
• Microfilament bundles in RAB5A gene over-expressed AGZY83-a cells were shown to be denser than in control cells using confocal laser scanning microscope (CLSM) [1].
• Rab5 regulates endocytic membrane traffic by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes [14].
• RIN3 expressed in HeLa cells localized to cytoplasmic vesicles and the RIN3-positive vesicles contained Rab5 but not the early endosomal marker EEA1 [15].
• Staphylococci-containing phagosomes were matured by sequential and dynamic interactions with Rab5- and Rab7-positive vesicles [16].

Associations of RAB5A with chemical compounds

• We propose that Rab5-dependent formation of membrane domains enriched in phosphatidylinositol-3-phosphate has evolved as a mechanism for the recruitment of multiple effector proteins to mammalian early endosomes, and that these domains are multifunctional, depending on the differing activities of the effector proteins recruited [14].
• Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor [17].
• Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway [18].
• Immune complexes of native tuberin, as well as recombinant protein, possessed activity to stimulate GTP hydrolysis of Rab5 [19].
• This was dependent on the presence of active forms of Rab5 and the generation of PtdIns 3-P-enriched platforms on early endosomess [20].

Physical interactions of RAB5A

• RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway [15].
• Rabaptin-5 also binds the active form of GTPase Rab5 [19].
• Large changes in the intrinsic tryptophan fluorescence of Rab5 accompany binding to the C(2)H(2) Zn(2+) finger of EEA1 [21].
• REP15 interacts directly with Rab15-GTP but not with Rab5 or Rab11 [22].
• In stark contrast to the helix-dominated, Rab-binding domains previously reported, APPL1 PH domain employs beta-strands to interact with Rab5 [23].

Enzymatic interactions of RAB5A

• An increase in beta-cleaved soluble APP relative to alpha-cleaved soluble APP was also observed following Rab5 overexpression [24].

Co-localisations of RAB5A

• Confocal immunofluorescence microscopy of transfected HEp2 cells revealed that the C-terminal part (residues 1277-1411) of EEA1 colocalizes extensively with a GTPase-deficient mutant of the early endosomal GTPase Rab5, while deletion of the FYVE finger or mutations that interfere with zinc binding cause a cytosolic localization [25].

Regulatory relationships of RAB5A

• Endocytosis of epidermal growth factor receptor regulated by Grb2-mediated recruitment of the Rab5 GTPase-activating protein RN-tre [10].
• In addition, both dynamin2 K44A and Rab5 S34N mildly inhibited LPA1-dependent activation of serum response factor [18].
• We conclude that wortmannin alters intracellular trafficking of EGFR by activating Rab5 rather than by inhibiting PI3K [26].
• RIN1 is also shown to stimulate Rab5 guanine nucleotide exchange, Rab5A-dependent endosome fusion, and EGF receptor-mediated endocytosis [27].
• The mutant full-length EEA1 caused the accumulation of endosome clusters and suppressed the enlargement of endosomes caused by a persistently active form of Rab5 (Rab5Q79L) [28].

Other interactions of RAB5A

• The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5 [29].
• Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain [14].
• Here, we demonstrate that Grb2 also signals to Rab5, a small GTPase that plays a key role in early endocytic trafficking [10].
• It has been reported that phosphatidylinositol 3-kinases and FYVE domain proteins, such as EEA1, can be recruited onto early endosomes and act as Rab5 effectors [11].
• These results indicate that RIN3 biochemically characterized as the stimulator and stabilizer for GTP-Rab5 plays an important role in the transport pathway from plasma membrane to early endosomes [15].

Analytical, diagnostic and therapeutic context of RAB5A

• Cell fractionation experiments confirm these results; i.e., the MNK protein is recruited to the endosomal fraction on copper stimulation and colocalizes with Rab5 and Rab7 proteins [30].
• We also detected the difference in RAB5A gene expression at RNA level in human non-small cell lung carcinoma by RT-PCR [2].
• From sequence alignments and molecular modelling we identified structural elements that might contribute to the definition of the functional specificity of rab5 [31].
• Molecular cloning of Rab5 (ApRab5) in Aiptasia pulchella and its retention in phagosomes harboring live zooxanthellae [32].
• In the first assay, the ability of p85 to bind to Rab5 is measured using an enzyme-linked immunosorbent assay (ELISA) [33].

References