Acts as a GTPase-activating protein for RAB5A and RAB43. Involved in receptor trafficking. In complex with EPS8 inhibits internalization of EGFR. Involved in retrograde transport from the endocytic pathway to the Golgi apparatus. Involved in the transport of Shiga toxin from early and recycling endosomes to the trans-Golgi network. Required for structural integrity of the Golgi complex. (updated: Oct. 10, 2018)
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
No sequence conservation computed yet.
This protein is annotated as membranous in Gene Ontology.
Total structural coverage: 0%
No model available.
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The reference OMIM entry for this protein is 605405
Usp6 n-terminal-like; usp6nl
Related to the n terminus of tre; rntre
CLONING
By sequencing cDNAs randomly selected from a cDNA library derived from the human immature myeloid cell line KG-1, Nomura et al. (1994) isolated a cDNA encoding a protein they designated KIAA0019. Matoskova et al. (1996) identified a cDNA encoding KIAA0019 by searching for cDNAs encoding proteins that bind to the SH3 domain of EPS8 (
600206). Because the 828-amino acid protein encoded by this cDNA shows homology to the N-terminal region of the TRE oncogene (see
604334), the authors designated it RNTRE, for 'related to the N terminus of TRE.' RNTRE was shown to be ubiquitously expressed. The regional homology between RNTRE and TRE, which is limited to their N-terminal portion, prompted Matoskova et al. (1996) to investigate the origin of the TRE oncogene transcriptional unit. They showed that TRE is the fusion product of a 5-prime genetic element homologous to RNTRE and a 3-prime element encoding a deubiquitinating enzyme. Moreover, they identified within the N terminus of RNTRE and TRE a TRE homology (TRH) domain, which is conserved within several proteins from yeast to mammal and has protein-binding properties in vitro.
GENE FUNCTION
Matoskova et al. (1996) demonstrated that the product of the RNTRE gene is a 97- to 100-kD protein that stably associates in vivo and in vitro with EPS8 via the SH3 domain of the latter. In vitro, RNTRE displayed remarkable preference for binding to the SH3 domain of EPS8, compared with 8 other SH3s. A C-terminal truncated mutant of RNTRE was able to confer proliferative advantage and reduced serum requirement to NIH 3T3 fibroblasts, suggesting a role for RNTRE in cell proliferation. Epidermal growth factor receptor (EGFR;
131550) signaling involves small GTPases of the Rho family, and EGFR trafficking involves small GTPases of the Rab family. Lanzetti et al. (2000) reported that the EPS8 protein connects these signaling pathways. EPS8 is a substrate of EGFR that is held in a complex with SOS1 (
182530) by the adaptor protein E3B1 (
603050), thereby mediating activation of RAC (
602048). Through its SH3 domain, EPS8 interacts with RNTRE. Lanzetti et al. (2000) showed that RNTRE is a RAB5 (
179512) GTPase-activating protein (GAP) whose activity is regulated by EGFR. By entering in a complex with EPS8, RNTRE acts on RAB5 and inhibits internalization of the EGFR. Furthermore, RNTRE diverts EPS8 from its RAC-activating function, resulting in the attenuation of RAC signaling. Thus, depending on its state of association with E3B1 or RNTRE, EPS8 participates in both EGFR signaling through RAC and EGFR trafficking through RAB5. Lanzetti et al. (2000) showed that 2 arginine residues (arg106 and arg150 of RNTRE) are highly conserved in TRH domains. In addition, an aspartate residue (asp147 of RNTRE) is invariant. Mutations of any of these residues to alanine resulted in proteins that were unable to display GAP activity on RAB5. Lanzetti et al. (2004) demonstrated that RAB5 is indispensable for a form of receptor tyrosine kinase-induced actin remodeling called circular ruffling. Three independent signals, originating from RAB5, phosphatidylinositol-3-hydroxykinase, and RAC (see
602048), respectively, are simultaneously required for the induction of circular ruffles. RAB5 signals to the actin cytoskeleton through RNTRE, a RAB5-specific GTPase-activating protein (GAP). Lanzetti et al. (2004) demonstrated that RNTRE has the dual function of RAB5-GAP and RAB5 effector. They also showed that RNTRE ...
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Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 605405 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).