RAB7A

Ras-related protein Rab-7a is a is_associated_with::protein that in humans is encoded by the RAB7A is_associated_with::gene.

Ras-related protein Rab-7a is involved in is_associated_with::endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the is_associated_with::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.

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

Function


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 is_associated_with::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 is_associated_with::Helicobacter pylori.

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 is_associated_with::melanosomes through modulation of is_associated_with::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 as it plays a role in the long-range retrograde transport of signalling is_associated_with::endosomes in the is_associated_with::axons.

Gene


The RAB7A gene is located on chromosome 3 in humans, specifically on the long q arm from is_associated_with::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. In 1995 it had been mapped to chromosome 9 in mice by Barbosa et al. Finally, using is_associated_with::fluorescence in situ hybridization (FISH), Kashuba et al. were able to map the RAB7A gene to 3q21 in 1997.

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.

Regulation


It is linked that RAB7a levels and function were independent of is_associated_with::melanocyte lineage-specific is_associated_with::transcription factors (MITF) but recent research has shown that is_associated_with::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 is_associated_with::antisense RNA, downregulation of RAB7 gene expression in is_associated_with::HeLa cells using antisense RNA induces severe cell vacuolation that resembles the is_associated_with::phenotype seen in is_associated_with::fibroblasts from patients with is_associated_with::Chédiak–Higashi syndrome.

In the presence of is_associated_with::growth factor, is_associated_with::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 is_associated_with::glucose and is_associated_with::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.

Interactions
RAB7A has been shown to interact with RILP and CHM. 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 is_associated_with::cytoskeleton. RILP plays the role of a downstream effector for Rab7 and together both of these proteins act to regulate late endocytic traffic.

Other key interactions include is_associated_with::RAC1 (By similarity), NTRK1/TRKA (By similarity), is_associated_with::C9orf72 (By similarity), CHM (the substrate-binding subunit of the Rab geranylgeranyltransferase complex), and RILP, as well as is_associated_with::PSMA7, is_associated_with::RNF115 and is_associated_with::FYCO1. Interacts with the PIK3C3/VPS34-PIK3R4 complex. The GTP-bound form interacts with is_associated_with::OSBPL1A and is_associated_with::CLN3.

Clinical significance
RAB7 is a small is_associated_with::GTPase that has the potential of causing is_associated_with::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 is_associated_with::genes, which is a member of the RAS is_associated_with::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 is_associated_with::GTP and is_associated_with::GDP molecules.

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 is_associated_with::gene cluster. Lysosomal-associated degradation, a universal feature of is_associated_with::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. 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.

Charcot-Marie-Tooth 2B
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. is_associated_with::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 is_associated_with::muscular dystrophy.