RAB7A

Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.[5][6]

RAB7A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1T91, 1YHN, 3LAW
Identifiers
Aliases	RAB7A, PRO2706, RAB7, member RAS oncogene family, CMT2B
External IDs	OMIM: 602298 MGI: 105068 HomoloGene: 3408 GeneCards: RAB7A
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q21.3 Start 128,726,183 bp[1] End 128,814,798 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 D1|6 39.13 cM Start 87,999,106 bp[2] End 88,045,270 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • GTP binding • GO:0001948 protein binding • retromer complex binding • GTPase activity • GDP binding • Rac GTPase binding Cellular component • cytoplasm • pre-autophagosomal structure membrane • endosome • phagocytic vesicle membrane • Golgi apparatus • late endosome • membrane • late endosome membrane • extrinsic component of lysosome membrane • lipid droplet • melanosome membrane • Retromer • lysosomal membrane • autophagosome membrane • phagocytic vesicle • lysosome • extracellular exosome • cytoplasmic vesicle • cytosol • cell membrane • endosome membrane • secretory granule membrane • terminal bouton • alveolar lamellar body • vacuolar membrane • intracellular Biological process • protein to membrane docking • protein targeting to lysosome • lipophagy • viral shedding • positive regulation of protein catabolic process • phagosome-lysosome fusion • endocytosis • antigen processing and presentation of exogenous peptide antigen via MHC class II • lipid metabolism • endosome to lysosome transport • phagosome acidification • autophagy • lipid catabolic process • phagosome maturation • early endosome to late endosome transport • retrograde transport, endosome to Golgi • protein transport • positive regulation of exosomal secretion • epidermal growth factor catabolic process • positive regulation of viral process • neutrophil degranulation • negative regulation of exosomal secretion • negative regulation of intralumenal vesicle formation • autophagosome assembly • bone resorption • transport • intracellular protein transport • Rab protein signal transduction • small GTPase mediated signal transduction Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7879	19349
Ensembl	ENSG00000075785	ENSMUSG00000079477
UniProt	P51149	P51150
RefSeq (mRNA)	NM_004637	NM_001293652 NM_001293653 NM_001293654 NM_001293655 NM_009005
RefSeq (protein)	NP_004628	NP_001280581 NP_001280582 NP_001280583 NP_001280584 NP_033031
Location (UCSC)	Chr 3: 128.73 – 128.81 Mb	Chr 6: 88 – 88.05 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Ras-related protein Rab-7a is involved in endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the cell membrane around a substance outside of the cell (for example a protein) and then forms a vesicle. The vesicle is then brought into the cell and cleaved from the cell membrane. RAB7A plays an important role in the movement of vesicles into the cell as well as with vesicle trafficking.[7]

Various mutations of RAB7A are associated with Hereditary sensory neuropathy type 1C (HSN IC), also known as Charcot-Marie-Tooth syndrome type 2B (CMT2B).[8]

Function

Shows the role of RAB7 during endocytosis

Members of the RAB family of RAS-related GTP-binding proteins are important regulators of vesicular transport and are located in specific intracellular compartments. RAB7 has been localized to late endosomes and shown to be important in the late endocytic pathway. In addition, it has been shown to have a fundamental role in the cellular vacuolation induced by the cytotoxin VacA of Helicobacter pylori.[9]

RAB7A functions as a key regulator in endo-lysosomal trafficking, governs early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positions, and endosome-lysosome transport through different protein-protein interaction cascades.

RAB7A is also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes through modulation of SOX10 and the oncogene MYC. Mutations in the lysosomal pathway result in tumor progression in melanoma cells.

Tissue distribution

RAB7 is widely expressed; high expression found in skeletal muscle[10] as it plays a role in the long-range retrograde transport of signalling endosomes in the axons.

Gene

Obtained from U.S. National Library of Medicine at the link http://ghr.nlm.nih.gov/gene/RAB7A

The RAB7A gene is located on chromosome 3 in humans, specifically on the long q arm from base pair 128,726,135 to 128,814,797. The location was found using mapping which was first done by Davies et al. in 1997 to map the RAB7A gene to chromosome 3 using PCR analysis.[5] In 1995 it had been mapped to chromosome 9 in mice by Barbosa et al. Finally, using fluorescence in situ hybridization (FISH), Kashuba et al. were able to map the RAB7A gene to 3q21 in 1997.[6]

RAB7a was cloned by screening a human placenta cDNA library with a rat Rab7 cDNA to show that the RAB7a cDNA encodes a 207-amino acid protein whose sequence is 99% identical to those of mouse, rat, and dog Rab7a and 61% identical to that of yeast Rab7a. Using Northern Blot Analysis, Vitelli et al. (1996) found that RAB7a was expressed as 1.7- and 2.5-kb transcripts in all cell lines examined but that there was a large difference in the total amount of RAB7a mRNA among the cell lines.[11]

Regulation

MYC and SOX10 regulate RAB7 in an oncogene- and lineage-dependent manner, respectively

It is linked that RAB7a levels and function were independent of melanocyte lineage-specific transcription factors (MITF) but recent research has shown that SOX10 (a neuroectodermal master modulator) and MYC (an oncogene) are the major regulators. Rab7a is regulated by SOX10 and MYC respectively in a lineage-specific wiring. Studies show that RAB7a can be specifically up regulated through MITF-independent manners like changing levels of SOX10 or MYC to affect tumor proliferation especially in melanoma^[14].

In studies using antisense RNA, downregulation of RAB7 gene expression in HeLa cells using antisense RNA induces severe cell vacuolation that resembles the phenotype seen in fibroblasts from patients with Chédiak–Higashi syndrome.[12]

In the presence of growth factor, growth factor inhibition of mammalian Rab7 had no effect on nutrient transporter expression in mouse pro-B-lymphocytic cells. In growth factor-deprived cells, however, blocking Rab7 function prevented the clearance of glucose and amino acid transporter proteins from the cell surface. When Rab7 was inhibited, growth factor-deprived cells maintained their mitochondrial membrane potential and displayed prolonged, growth factor-independent, nutrient-dependent cell survival. The authors concluded that RAB7 functions as a proapoptotic protein by limiting cell-autonomous nutrient uptake.[13]

Interactions

RAB7A has been shown to interact with RILP[14][15] and CHM.[16][17] RILP has been shown to have a key role in the control of transport to degradative compartments along with Rab7 and may link Rab7 function to the cytoskeleton. RILP plays the role of a downstream effector for Rab7 and together both of these proteins act to regulate late endocytic traffic.[18]

Other key interactions include RAC1 (By similarity), NTRK1/TRKA (By similarity), C9orf72 (By similarity), CHM (the substrate-binding subunit of the Rab geranylgeranyltransferase complex), and RILP,[19] as well as PSMA7, RNF115 and FYCO1. Interacts with the PIK3C3/VPS34-PIK3R4 complex. The GTP-bound form interacts with OSBPL1A and CLN3.[20] Rab7A was also shown to interact with the Retromer Complex, most likely through the Vps35 subunit.[21]

Clinical significance

RAB7 is a small GTPase that has the potential of causing malignancy from over 35 tumor types. It is found that RAB7 is an early induced melanoma driver whose levels can define metastatic risk. The RAB7A gene belongs to the RAB family of genes, which is a member of the RAS oncogene family. These genes in the RAB family provides the instructions that are necessary for making proteins for vesicle trafficking. These proteins are GTPases and act like switch which is turned on and off by GTP and GDP molecules.[7]

Melanoma

Melanoma cells retain a developmental memory that reflects a unique wiring of vesicles trafficking pathways. Rab7 is seen to control the proliferative and invasive potential of these aggressive tumors upon identification of melanoma enriched endolysosomal gene cluster. Lysosomal-associated degradation, a universal feature of eukaryotic cells, can be hijacked in a tumor-type- and stage –dependent manner. Finding that RAB7 is controlled by SOX10 and MYC in a MITF-independent manner has important basic and translational implications.[22] Sox10 is not inhibited by mechanisms that downregulate MITF, some of which including BRAF mutations, are relatively frequent in malignant melanomas. This may ensure a developmental memory in the expression of RAB7. It is speculated that downregulation of RAB7 in the invasive front of aggressive melanomas is modulated by epithelial-to-mesenchymal-like mechanisms, such as those recently described to underlie the transcriptional switch associated with prometastatic phenotypes. In otherwords, there is an inherent dependency of melanoma cells on the small GTPase RAB7, identified within a lysosomal gene cluster that distinguishes this malignancy from over 35 tumor types. Analyses in human cells, clinical specimens, and mouse models demonstrated that RAB7 is an early-induced melanoma driver whose levels can be tuned to favor tumor invasion, ultimately defining metastatic risk. Importantly, RAB7 levels and function were independent of MITF and instead, the neuroectodermal master modulator SOX10 and the oncogene MYC are key RAB7a regulators.[22]

Charcot-Marie-Tooth 2B

Charcot-marie-tooth foot

Also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA). This is a genetically and clinically heterogeneous group of inherited disorders, characterized by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement.[23][24] Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 23,000 people in the United Kingdom and 125,000 people in the United States. CMT was previously classified as a subtype of muscular dystrophy.[25]

References

1. GRCh38: Ensembl release 89: ENSG00000075785 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000079477 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Davies JP, Cotter PD, Ioannou YA (Apr 1997). "Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene". Genomics. 41 (1): 131–4. doi:10.1006/geno.1997.4644. PMID 9126495.
6. Kashuba VI, Gizatullin RZ, Protopopov AI, Allikmets R, Korolev S, Li J, Boldog F, Tory K, Zabarovska V, Marcsek Z, Sumegi J, Klein G, Zabarovsky ER, Kisselev L (Dec 1997). "NotI linking/jumping clones of human chromosome 3: mapping of the TFRC, RAB7 and HAUSP genes to regions rearranged in leukemia and deleted in solid tumors". FEBS Letters. 419 (2–3): 181–5. doi:10.1016/S0014-5793(97)01449-X. PMID 9428630.
7. "RAB7A Genetics Home Reference". U.S. National Library of Medicine. Retrieved 21 October 2014.
8. Auer-Grumbach M (March 2008). "Hereditary sensory neuropathy type I". Orphanet Journal of Rare Diseases. 3 (7): 7. doi:10.1186/1750-1172-3-7. PMC 2311280. PMID 18348718.
9. "Entrez Gene: RAB7A RAB7A, member RAS oncogene family".
10. Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V (Mar 2003). "Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy". American Journal of Human Genetics. 72 (3): 722–727. doi:10.1086/367847. PMC 1180247. PMID 12545426.
11. Vitelli R, Chiariello M, Lattero D, Bruni CB, Bucci C (Dec 1996). "Molecular cloning and expression analysis of the human Rab7 GTP-ase complementary deoxyribonucleic acid". Biochemical and Biophysical Research Communications. 229 (3): 887–890. doi:10.1006/bbrc.1996.1897. PMID 8954989.
12. Davies JP, Cotter PD, Ioannou YA (Apr 1997). "Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene". Genomics. 41 (1): 131–134. doi:10.1006/geno.1997.4644. PMID 9126495.
13. Edinger AL, Cinalli RM, Thompson CB (Oct 2003). "Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression". Developmental Cell. 5 (4): 571–82. doi:10.1016/s1534-5807(03)00291-0. PMID 14536059.
14. Cantalupo G, Alifano P, Roberti V, Bruni CB, Bucci C (Feb 2001). "Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes". The EMBO Journal. 20 (4): 683–93. doi:10.1093/emboj/20.4.683. PMC 145419. PMID 11179213.
15. Caplan S, Hartnell LM, Aguilar RC, Naslavsky N, Bonifacino JS (Jul 2001). "Human Vam6p promotes lysosome clustering and fusion in vivo". The Journal of Cell Biology. 154 (1): 109–22. doi:10.1083/jcb.200102142. PMC 2196876. PMID 11448994.
16. Rak A, Pylypenko O, Niculae A, Goody RS, Alexandrov K (Jan 2003). "Crystallization and preliminary X-ray diffraction analysis of monoprenylated Rab7 GTPase in complex with Rab escort protein 1". Journal of Structural Biology. 141 (1): 93–5. doi:10.1016/S1047-8477(02)00634-2. PMID 12576024.
17. Alexandrov K, Simon I, Iakovenko A, Holz B, Goody RS, Scheidig AJ (Apr 1998). "Moderate discrimination of REP-1 between Rab7 x GDP and Rab7 x GTP arises from a difference of an order of magnitude in dissociation rates". FEBS Letters. 425 (3): 460–4. doi:10.1016/S0014-5793(98)00290-7. PMID 9563513.
18. Wu M, Wang T, Loh E, Hong W, Song H (Apr 2005). "Structural basis for recruitment of RILP by small GTPase Rab7". The EMBO Journal. 24 (8): 1491–1501. doi:10.1038/sj.emboj.7600643. PMC 1142575. PMID 15933719.
19. Wang T, Wong KK, Hong W (Feb 2004). "A unique region of RILP distinguishes it from its related proteins in its regulation of lysosomal morphology and interaction with Rab7 and Rab34". Molecular Biology of the Cell. 15 (2): 815–826. doi:10.1091/mbc.E03-06-0413. PMC 329395. PMID 14668488.
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21. Rojas R, van Vlijmen T, Mardones GA, Prabhu Y, Rojas AL, Mohammed S, Heck AJ, Raposo G, van der Sluijs P, Bonifacino JS (Nov 2008). "Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7". The Journal of Cell Biology. 183 (3): 513–26. doi:10.1083/jcb.200804048. PMC 2575791. PMID 18981234.
22. Alonso-Curbelo D, Riveiro-Falkenbach E, Pérez-Guijarro E, Cifdaloz M, Karras P, Osterloh L, Megías D, Cañón E, Calvo TG, Olmeda D, Gómez-López G, Graña O, Sánchez-Arévalo Lobo VJ, Pisano DG, Wang HW, Ortiz-Romero P, Tormo D, Hoek K, Rodríguez-Peralto JL, Joyce JA, Soengas MS (Jul 2014). "RAB7 controls melanoma progression by exploiting a lineage-specific wiring of the endolysosomal pathway". Cancer Cell. 26 (1): 61–76. doi:10.1016/j.ccr.2014.04.030. PMID 24981740.
23. "Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease". Medscape. Retrieved 4 November 2014.
24. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J, Shy ME (Jul 2000). "Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A". Brain. 123 (7): 1516–27. doi:10.1093/brain/123.7.1516. PMID 10869062.
25. Janssens K, Goethals S, Atkinson D, Ermanoska B, Fransen E, Jordanova A, Auer-Grumbach M, Asselbergh B, Timmerman V (May 2014). "Human Rab7 mutation mimics features of Charcot-Marie-Tooth neuropathy type 2B in Drosophila". Neurobiology of Disease. 65: 211–9. doi:10.1016/j.nbd.2014.01.021. PMID 24521780.

External links

• GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2