Ras-related protein Rab

Function

Ras-related protein Rab belongs to the Rab family of the small GTPase superfamily. It is associated with both constitutive and regulated secretory pathways and with pathways regulating protein traffic. Rab cycles between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors responsible for vesicle formation, movement, tethering and fusion.

• Rab-1A is required in stress-induced autophagy^[1].
• Rab-1B is required for secretion.
• Rab-2B regulates Golgi morphology^[2].
• Rab-3A is abundant in the brain and plays a role in recruitment of synaptic vesicles for exocytosis^[3].
• Rab-3B is essential for the transportation and secretion within cells and its expression is linked to progression of various malignancies^[4].
• Rab-3C promotes vesicle formation and packaging^[5].
• Rab-3D regulates intracellular vesicle transport during exocytosis^[6].
• Rab-4 regulates recycling vesicle formation^[7].
• Rab-5A regulates early endosome fusion^[8].
• Rab-6A regulates vesicular trafficking within the Golgi and non-Golgi compartments^[9].
• Rab-7A organises the endosomal-lysosomal system^[10].
• Rab-8A is the mitochondrial receptor for lipid droplets in muscle^[11].
• Rab-9A regulates cargo delivery to maturing melanosomes^[12].
• Rab-10 involved in multiple cellular pathways^[13].
• Rab-11A regulates vascular endothelial cadherin recycling and transferrin trafficking^[14].
• Rab-11B regulates transferrin and integrin trafficking^[15].
• Rab-12 regulates degradation of transferrin receptor and of amino acid transporter^[16], .^[17].
• Rab-18 controls lipid droplets growth and maturation^[18].
• Rab-21 plays an essential role in membrane transport including endocytosis and autophagy^[19].
• Rab-22 controls endosomal membrane trafficking^[20].
• Rab-23 regulates hedgehog signaling^[21].
• Rab-25 confers resistance to chemotherapy^[22].
• Rab-26 regulates autophagic degradation^[23].
• Rab-27A and Fab-27B regulate different steps of the exosome secretion pathway^[24].
• Rab-31 marks and controls ESCRT-independent exoxome pathway^[25].
• Rab-32 regulates lysosomal mTOR trafficking^[26].
• Rab-33 is involved in membrane trafficking and macroautophagy^[27].
• Rab-35 regulates the initial phase of phagosome maturation^[28].
• Rab-43 regulates the trafficking of adrenergic receptor and acetylcholine receptor in primary neutrons^[29].

Disease

Rab-11A, Rab-11B and Rab-25 are associated with Alzheimer disease, Huntington disease, type 2 diabetes and cancer^[30].

Structural highlights

Rab-11A undergoes a conformation change of between its inactive GDP-bound structure and its active GTP-bound structure. located at the surface of the protein^[31]. Water molecules are shown as red spheres.

3D structures of Rat-related protein Rab

Ras-related protein Rab 3D structures

References

1. ↑ Gyurkovska V, Murtazina R, Zhao SF, Shikano S, Okamoto Y, Segev N. Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence. Life Sci Alliance. 2023 Feb 13;6(5):e202201810. PMID:36781179 doi:10.26508/lsa.202201810
2. ↑ Aizawa M, Fukuda M. Small GTPase Rab2B and Its Specific Binding Protein Golgi-associated Rab2B Interactor-like 4 (GARI-L4) Regulate Golgi Morphology. J Biol Chem. 2015 Sep 4;290(36):22250-61. PMID:26209634 doi:10.1074/jbc.M115.669242
3. ↑ Geppert M, Bolshakov VY, Siegelbaum SA, Takei K, De Camilli P, Hammer RE, Südhof TC. The role of Rab3A in neurotransmitter release. Nature. 1994 Jun 9;369(6480):493-7. PMID:7911226 doi:10.1038/369493a0
4. ↑ Liu XS, Chen YL, Chen YX, Wu RM, Tan F, Wang YL, Liu ZY, Gao Y, Pei ZJ. Pan-cancer analysis reveals correlation between RAB3B expression and tumor heterogeneity, immune microenvironment, and prognosis in multiple cancers. Sci Rep. 2024 Apr 30;14(1):9881. PMID:38688977 doi:10.1038/s41598-024-60581-x
5. ↑ Chang YC, Li CH, Chan MH, Fang CY, Zhang ZX, Chen CL, Hsiao M. Overexpression of synaptic vesicle protein Rab GTPase 3C promotes vesicular exocytosis and drug resistance in colorectal cancer cells. Mol Oncol. 2023 Mar;17(3):422-444. PMID:36652260 doi:10.1002/1878-0261.13378
6. ↑ Millar AL, Pavios NJ, Xu J, Zheng MH. Rab3D: a regulator of exocytosis in non-neuronal cells. Histol Histopathol. 2002;17(3):929-36. PMID:12168804 doi:10.14670/HH-17.929
7. ↑ Mohrmann K, Gerez L, Oorschot V, Klumperman J, van der Sluijs P. Rab4 function in membrane recycling from early endosomes depends on a membrane to cytoplasm cycle. J Biol Chem. 2002 Aug 30;277(35):32029-35. PMID:12036958 doi:10.1074/jbc.M203064200
8. ↑ Khan FI, Aamir M, Wei DQ, Ahmad F, Hassan MI. Molecular mechanism of Ras-related protein Rab-5A and effect of mutations in the catalytically active phosphate-binding loop. J Biomol Struct Dyn. 2017 Jan;35(1):105-118. PMID:26727234 doi:10.1080/07391102.2015.1134346
9. ↑ Del Nery E, Miserey-Lenkei S, Falguières T, Nizak C, Johannes L, Perez F, Goud B. Rab6A and Rab6A' GTPases play non-overlapping roles in membrane trafficking. Traffic. 2006 Apr;7(4):394-407. PMID:16536738 doi:10.1111/j.1600-0854.2006.00395.x
10. ↑ Sun M, Luong G, Plastikwala F, Sun Y. Control of Rab7a activity and localization through endosomal type Igamma PIP 5-kinase is required for endosome maturation and lysosome function. FASEB J. 2020 Feb;34(2):2730-2748. PMID:31908013 doi:10.1096/fj.201901830R
11. ↑ Ouyang Q, Chen Q, Ke S, Ding L, Yang X, Rong P, Feng W, Cao Y, Wang Q, Li M, Su S, Wei W, Liu M, Liu J, Zhang X, Li JZ, Wang HY, Chen S. Rab8a as a mitochondrial receptor for lipid droplets in skeletal muscle. Dev Cell. 2023 Feb 27;58(4):289-305.e6. PMID:36800997 doi:10.1016/j.devcel.2023.01.007
12. ↑ Mahanty S, Ravichandran K, Chitirala P, Prabha J, Jani RA, Setty SR. Rab9A is required for delivery of cargo from recycling endosomes to melanosomes. Pigment Cell Melanoma Res. 2016 Jan;29(1):43-59. PMID:26527546 doi:10.1111/pcmr.12434
13. ↑ Chua CEL, Tang BL. Rab 10-a traffic controller in multiple cellular pathways and locations. J Cell Physiol. 2018 Sep;233(9):6483-6494. PMID:29377137 doi:10.1002/jcp.26503
14. ↑ Yan Z, Wang ZG, Segev N, Hu S, Minshall RD, Dull RO, Zhang M, Malik AB, Hu G. Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function. Arterioscler Thromb Vasc Biol. 2016 Feb;36(2):339-49. PMID:26663395 doi:10.1161/ATVBAHA.115.306549
15. ↑ Howe EN, Burnette MD, Justice ME, Schnepp PM, Hedrick V, Clancy JW, Guldner IH, Lamere AT, Li J, Aryal UK, D'Souza-Schorey C, Zartman JJ, Zhang S. Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth. Nat Commun. 2020 Jun 15;11(1):3017. PMID:32541798 doi:10.1038/s41467-020-16832-2
16. ↑ Matsui T, Itoh T, Fukuda M. Small GTPase Rab12 regulates constitutive degradation of transferrin receptor. Traffic. 2011 Oct;12(10):1432-43. doi: 10.1111/j.1600-0854.2011.01240.x. Epub, 2011 Jul 29. PMID:21718402 doi:http://dx.doi.org/10.1111/j.1600-0854.2011.01240.x
17. ↑ Matsui T, Fukuda M. Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4. EMBO Rep. 2013 May;14(5):450-7. PMID:23478338 doi:10.1038/embor.2013.32
18. ↑ Xu D, Li Y, Wu L, Li Y, Zhao D, Yu J, Huang T, Ferguson C, Parton RG, Yang H, Li P. Rab18 promotes lipid droplet (LD) growth by tethering the ER to LDs through SNARE and NRZ interactions. J Cell Biol. 2018 Mar 5;217(3):975-995. PMID:29367353 doi:10.1083/jcb.201704184
19. ↑ Li X, Ni J, Qing H, Quan Z. The Regulatory Mechanism of Rab21 in Human Diseases. Mol Neurobiol. 2023 Oct;60(10):5944-5953. PMID:37369821 doi:10.1007/s12035-023-03454-0
20. ↑ Kauppi M, Simonsen A, Bremnes B, Vieira A, Callaghan J, Stenmark H, Olkkonen VM. The small GTPase Rab22 interacts with EEA1 and controls endosomal membrane trafficking. J Cell Sci. 2002 Mar 1;115(Pt 5):899-911. PMID:11870209 doi:10.1242/jcs.115.5.899
21. ↑ Evans TM, Ferguson C, Wainwright BJ, Parton RG, Wicking C. Rab23, a negative regulator of hedgehog signaling, localizes to the plasma membrane and the endocytic pathway. Traffic. 2003 Dec;4(12):869-84. PMID:14617350 doi:10.1046/j.1600-0854.2003.00141.x
22. ↑ Temel SG, Giray A, Karakas B, Gul O, Kozanoglu I, Celik H, Basaga H, Acikbas U, Sucularli C, Oztop S, Aka Y, Kutuk O. RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells. Apoptosis. 2020 Dec;25(11-12):799-816. PMID:32901335 doi:10.1007/s10495-020-01635-z
23. ↑ Liu H, Zhou Y, Qiu H, Zhuang R, Han Y, Liu X, Qiu X, Wang Z, Xu L, Tan R, Hong W, Wang T. Rab26 suppresses migration and invasion of breast cancer cells through mediating autophagic degradation of phosphorylated Src. Cell Death Dis. 2021 Mar 17;12(4):284. PMID:33731709 doi:10.1038/s41419-021-03561-7
24. ↑ Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010 Jan;12(1):19-30; sup pp 1-13. PMID:19966785 doi:10.1038/ncb2000
25. ↑ Wei D, Zhan W, Gao Y, Huang L, Gong R, Wang W, Zhang R, Wu Y, Gao S, Kang T. RAB31 marks and controls an ESCRT-independent exosome pathway. Cell Res. 2021 Feb;31(2):157-177. PMID:32958903 doi:10.1038/s41422-020-00409-1
26. ↑ Drizyte-Miller K, Chen J, Cao H, Schott MB, McNiven MA. The small GTPase Rab32 resides on lysosomes to regulate mTORC1 signaling. J Cell Sci. 2020 Jun 11;133(11):jcs236661. PMID:32295849 doi:10.1242/jcs.236661
27. ↑ Morgan NE, Cutrona MB, Simpson JC. Multitasking Rab Proteins in Autophagy and Membrane Trafficking: A Focus on Rab33b. Int J Mol Sci. 2019 Aug 12;20(16):3916. PMID:31408960 doi:10.3390/ijms20163916
28. ↑ Haley R, Zhou Z. The small GTPase RAB-35 facilitates the initiation of phagosome maturation and acts as a robustness factor for apoptotic cell clearance. Small GTPases. 2021 May;12(3):188-201. PMID:31607221 doi:10.1080/21541248.2019.1680066
29. ↑ Wei Z, Xu X, Fang Y, Khater M, Naughton SX, Hu G, Terry AV Jr, Wu G. Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein-coupled receptors. J Biol Chem. 2021 Jan-Jun;296:100517. PMID:33676895 doi:10.1016/j.jbc.2021.100517
30. ↑ Bhuin T, Roy JK. Rab11 in disease progression. Int J Mol Cell Med. 2015 Winter;4(1):1-8. PMID:25815277
31. ↑ Pasqualato S, Senic-Matuglia F, Renault L, Goud B, Salamero J, Cherfils J. The structural GDP/GTP cycle of Rab11 reveals a novel interface involved in the dynamics of recycling endosomes. J Biol Chem. 2004 Mar 19;279(12):11480-8. Epub 2003 Dec 29. PMID:14699104 doi:10.1074/jbc.M310558200