RAB8A

Summary

RAB8A (RAB8A, member RAS oncogene family, HGNC:7007) is a protein-coding gene on chromosome 19p13.11, encoding Ras-related protein Rab-8A (P61006). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

The protein encoded by this gene is a member of the RAS superfamily which are small GTP/GDP-binding proteins with an average size of 200 amino acids. The RAS-related proteins of the RAB/YPT family may play a role in the transport of proteins from the endoplasmic reticulum to the Golgi and the plasma membrane. This protein shares 97%, 96%, and 51% similarity with the dog RAB8, mouse MEL, and mouse YPT1 proteins, respectively and contains the 4 GTP/GDP-binding sites that are present in all the RAS proteins. The putative effector-binding site of this protein is similar to that of the RAB/YPT proteins. However, this protein contains a C-terminal CAAX motif that is characteristic of many RAS superfamily members but which is not found in YPT1 and the majority of RAB proteins. Although this gene was isolated as a transforming gene from a melanoma cell line, no linkage between MEL and malignant melanoma has been demonstrable. This oncogene is located 800 kb distal to MY09B on chromosome 19p13.1.

Source: NCBI Gene 4218 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 13 total
• Druggable target: yes
• MANE Select transcript: NM_005370

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7007
Approved symbol	RAB8A
Name	RAB8A, member RAS oncogene family
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	RAB8
Ensembl gene	ENSG00000167461
Ensembl biotype	protein_coding
OMIM	165040
Entrez	4218

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000300935, ENST00000586682, ENST00000587156, ENST00000588105, ENST00000589697, ENST00000590899, ENST00000592971, ENST00000860859, ENST00000860860, ENST00000860861, ENST00000923015

RefSeq mRNA: 1 — MANE Select: NM_005370 NM_005370

CCDS: CCDS12339

Canonical transcript exons

ENST00000300935 — 8 exons

Exon	Start	End
ENSE00001113278	16127437	16127526
ENSE00001113280	16128026	16128091
ENSE00001131325	16111889	16112025
ENSE00001277163	16132212	16134234
ENSE00003517961	16118226	16118286
ENSE00003599877	16125470	16125547
ENSE00003649015	16121750	16121810
ENSE00003672157	16129554	16129604

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.3255 / max 997.1908, expressed in 1823 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174380	66.2589	1822
174378	1.4961	560
174379	0.3451	137
174383	0.2253	73

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.44	gold quality
mononuclear cell	CL:0000842	97.31	gold quality
leukocyte	CL:0000738	97.29	gold quality
ileal mucosa	UBERON:0000331	96.93	gold quality
bone marrow cell	CL:0002092	96.85	gold quality
duodenum	UBERON:0002114	96.71	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.38	gold quality
colonic mucosa	UBERON:0000317	95.97	gold quality
jejunal mucosa	UBERON:0000399	95.87	gold quality
blood	UBERON:0000178	95.59	gold quality
colonic epithelium	UBERON:0000397	95.56	gold quality
granulocyte	CL:0000094	95.42	gold quality
penis	UBERON:0000989	95.24	gold quality
bone marrow	UBERON:0002371	95.15	gold quality
islet of Langerhans	UBERON:0000006	95.07	gold quality
calcaneal tendon	UBERON:0003701	94.83	gold quality
caecum	UBERON:0001153	94.78	gold quality
stromal cell of endometrium	CL:0002255	94.72	gold quality
sural nerve	UBERON:0015488	94.72	gold quality
nipple	UBERON:0002030	94.70	gold quality
trachea	UBERON:0003126	94.57	gold quality
pylorus	UBERON:0001166	94.55	gold quality
pharyngeal mucosa	UBERON:0000355	94.53	gold quality
endometrium epithelium	UBERON:0004811	94.51	gold quality
vermiform appendix	UBERON:0001154	94.49	gold quality
pericardium	UBERON:0002407	94.45	gold quality
rectum	UBERON:0001052	94.34	gold quality
urethra	UBERON:0000057	94.32	gold quality
renal medulla	UBERON:0000362	94.14	gold quality
synovial joint	UBERON:0002217	94.07	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.97
E-MTAB-6911	no	646.34
E-MTAB-7303	no	134.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting RAB8A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6817-3P	99.79	68.35	2126

Literature-anchored findings (GeneRIF, showing 40)

• These findings establish Rab8 as a key component of the regulatory machinery that leads to ATP-binding cassette transporter A1 (ABCA1)-dependent removal of cholesterol from endocytic circuits. (PMID:17050734)
• MT1-MMP delivery to invasive structures, and therefore its proinvasive activity, is regulated by Rab8 GTPase. (PMID:17332756)
• Rab8a and Myosin Vb colocalize to a tubular network containing EHD1 and EHD3, which does not contain Rab11a. (PMID:17507647)
• One microvillus inclusion disease patient who shows an identical phenotype to Rab8-deficient mice expresses a reduced amount of RAB8A (PMID:17597763)
• Data show that the Rab8a, -17, and -23, and their cognate GTPase-activating proteins (GAPs), XM_037557, TBC1D7, and EVI5like, are involved in primary cilia formation, and that Rab8a specifically interacts with cenexin/ODF2. (PMID:17646400)
• in response to cellular activation in T cells and B cells, a PTB-containing stability complex forms that contains binding sites for Rab8A and cyclin D(2) transcripts and increases their mRNA half-lifes (PMID:18714005)
• data suggest that the function of Rab8 is important for DV2 infection, and Rab8 may be involved in DV2 infection. (PMID:18724065)
• Both CEP290 and PCM-1 are required for ciliogenesis and are involved in the ciliary targeting of Rab8. (PMID:18772192)
• Rab8 regulates ABCA1 cell surface expression and facilitates cholesterol efflux in primary human macrophages. (PMID:19304576)
• These data suggest that Myo5c associated with Rab8 is involved in the release of dengue virus 2 from HepG2 cells. (PMID:19641326)
• Rab11, in its GTP-bound form, interacts with Rabin8 and kinetically stimulates the guanine nucleotide-exchange activity of Rabin8 toward Rab8. (PMID:20308558)
• Data provide strong evidence indicating that Rab8 GTPase interacts with distinct motifs in the C termini of alpha(2B)-AR and beta(2)-AR and differentially modulates their traffic from the TGN to the cell surface. (PMID:20424170)
• RPGR modulates intracellular localization and function of RAB8A. (PMID:20631154)
• WNK1 promotes cell surface expression of glucose transporter GLUT1 by regulating a Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4)-Rab8A complex (PMID:20937822)
• Rab8A function is not needed for budding or motility of exocytotic carriers but is required for their docking and fusion. (PMID:21596566)
• DCDC5 colocalizes with Rab8 and links it to dynein during cytokinesis. (PMID:22159412)
• EPI64 regulates membrane trafficking both by stabilizing Arf6-GTP and by inhibiting the recycling of membrane through the tubular endosome by decreasing Rab8a-GTP levels. (PMID:22219378)
• Data suggest that the Rabin8-Rab8-Sec15 interaction may couple the activation of Rab8 to the recruitment of the Rab8 effector and is involved in the regulation of vesicular trafficking for primary cilium formation. (PMID:22433857)
• This study demonistrated that Rabin8 regulates spine development. (PMID:22445341)
• This article reviewes biophysical and structural work and discuss possible functional implications of the finding that Rab8 binds with the highest affinity to OCRL1 among the Rab proteins tested.[review] (PMID:22790198)
• Optineurin acts as an adaptor to bring together Rab8 and its GTPase-activating protein TBC1D17. (PMID:22854040)
• These findings show a role for Rab8a in the physiological function of hSVCT1 in intestinal epithelia. (PMID:23014846)
• Slp4 and Rab8 are expressed and interact in human platelets, and might be involved in dense granule release. (PMID:23140275)
• These experiments provide us with an understanding of the role Rab8 plays in coordinated regulation of mGluR1a and how this impacts mGluR1a signaling (PMID:23175844)
• Fuzzy appears to control subcellular localization of the core PCP protein Dishevelled, recruiting it to Rab8-positive vesicles and to the basal body and cilium. We show that loss of Fuzzy results in inhibition of PCP signaling (PMID:23303251)
• NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by triggering the switch in binding specificity of Rabin8 from PS to Sec15. (PMID:23435566)
• Rab5a, Rab8a and Rab14 are major regulators of MT1-MMP trafficking and invasive migration of primary human macrophages. (PMID:23606746)
• Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB. (PMID:24072714)
• Rab8a and Drebrin E act as key proteins in the regulation of apical trafficking in intestinal epithelial cells. (PMID:24399445)
• TRIM required LAX for binding to Rab8 in a complex, a novel CTLA-4/TRIM/LAX/Rab8 effector complex in the transport of CTLA-4 to the surfaces of T cells (PMID:24515439)
• Microvilli establishment required interaction between RAB8A and MYO5B, while loss of the interaction between RAB11A and MYO5B induced microvillus inclusions. (PMID:24892806)
• Study established a direct interaction between alpha-synclein and Rab8a and provided unique insights into the molecular mechanisms of alpha-synclein toxicity (PMID:24983211)
• High expression of RAB8A is associated with endometrial cancer. (PMID:25477298)
• DLC3 is recruited to Rab8-positive membrane tubules and is required for the integrity of the Rab8 and Golgi compartments. (PMID:25673874)
• the role of Rabin8 (a mammalian ortholog of Sec2p) with Rab8-nucleotide-exchange factor activity in autophagy in mammalian cells, was examined. (PMID:25787272)
• The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling T-cell receptors to the immune synapse. (PMID:26034069)
• Intercellular transfer of transferrin receptor by a contact-, Rab8-dependent mechanism involving tunneling nanotubes. (PMID:26220176)
• Rab8A GTPase Ser(111) phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser(111) phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser(65). (PMID:26471730)
• Further exploration of the NINL-associated interactome identifies MICAL3, a protein known to interact with Rab8 and to play an important role in vesicle docking and fusion. (PMID:26485645)
• Data demonstrate that EHBP1L1 links Rab8 and the Bin1-dynamin complex, which generates membrane curvature and excises the vesicle at the endocytic recycling compartment for apical transport. (PMID:26833786)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab8a	ENSDARG00000067920
mus_musculus	Rab8a	ENSMUSG00000003037
rattus_norvegicus	Rab8a	ENSRNOG00000014621

Paralogs (68): RAB27B (ENSG00000041353), RAB27A (ENSG00000069974), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB18 (ENSG00000099246), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB40AL (ENSG00000102128), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), RAB35 (ENSG00000111737), RAB23 (ENSG00000112210), DNAJC27 (ENSG00000115137), RAB29 (ENSG00000117280), RAB32 (ENSG00000118508), RAB14 (ENSG00000119396), RAB9B (ENSG00000123570), RAB9A (ENSG00000123595), RAB38 (ENSG00000123892), RAB22A (ENSG00000124209), RAB17 (ENSG00000124839), RAB2B (ENSG00000129472), RAB25 (ENSG00000132698), RAB33A (ENSG00000134594), RAB30 (ENSG00000137502), RAB1A (ENSG00000138069), RAB20 (ENSG00000139832), RAB15 (ENSG00000139998), RAB40B (ENSG00000141542), RAB13 (ENSG00000143545), RABL2A (ENSG00000144134), RAB5A (ENSG00000144566), RAB19 (ENSG00000146955)

Protein

Protein identifiers

Ras-related protein Rab-8A — P61006 (reviewed: P61006)

Alternative names: Oncogene c-mel

All UniProt accessions (1): P61006

UniProt curated annotations — full annotation on UniProt →

Function. The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. RAB8A is involved in polarized vesicular trafficking and neurotransmitter release. Together with RAB11A, RAB3IP, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis. Regulates the compacted morphology of the Golgi. Together with MYO5B and RAB11A participates in epithelial cell polarization. Also involved in membrane trafficking to the cilium and ciliogenesis. Together with MICALL2, may also regulate adherens junction assembly. May play a role in insulin-induced transport to the plasma membrane of the glucose transporter GLUT4 and therefore play a role in glucose homeostasis. Involved in autophagy. Participates in the export of a subset of neosynthesized proteins through a Rab8-Rab10-Rab11-dependent endososomal export route. Targeted to and stabilized on stressed lysosomes through LRRK2 phosphorylation. Suppresses stress-induced lysosomal enlargement through EHBP1 and EHNP1L1 effector proteins.

Subunit / interactions. Interacts (GTP-bound form) with MICALL1; regulates RAB8A association with recycling endosomes. Interacts with MICALL2; competes with RAB13 and is involved in E-cadherin endocytic recycling. Interacts (GTP-bound form) with MICAL1, MICALCL, MICAL3, EHBP1 and EHBP1L1; at least in case of MICAL1, MICALCL, MICAL3 and EHBP1L1 two molecules of RAB8A can bind to one molecule of the effector protein; ternary complexes of RAB8A, RAB13 and either MICAL1 or EHBP1L1 are possible. Interacts with EHD1. Interacts with MAP4K2 and SYTL4. Interacts with SGSM1 and SGSM3. Interacts with RABIF, RIMS2, RPH3A and RPH3A. Interacts with OPTN. Interacts with RAB3IP, RAB3IP functions as guanine exchange factor (GEF). Interacts with MYO5B. Interacts with CIMAP3. Interacts with BIRC6/bruce. Interacts with OCRL. Interacts with AHI1. Interacts with DCDC1. Interacts with LRRK2; interaction facilitates phosphorylation of Thr-72. Interacts with RAB31P, GDI1, GDI2, CHM, CHML, RABGGTA, RABGGTB, TBC1D15 and INPP5B; these interactions are dependent on Thr-72 not being phosphorylated. Interacts with RILPL1 and RILPL2; these interactions are dependent on the phosphorylation of Thr-72 by LRRK2. Interacts with DZIP1; prevents inhibition by the GDP-dissociation inhibitor GDI2. Interacts (in GDP-bound form) with RAB3IP/Rabin8, RAB3IP functions as guanine exchange factor (GEF) towards RAB8A. Interacts (in GDP-bound form) with RPGR, RPGR functions as GEF towards RAB8A.

Subcellular location. Cell membrane. Golgi apparatus. Endosome membrane. Recycling endosome membrane. Cell projection. Cilium. Cytoplasmic vesicle. Phagosome. Phagosome membrane. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole. Cilium basal body. Midbody. Cilium axoneme. Lysosome.

Post-translational modifications. Phosphorylation of Thr-72 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2. Phosphorylation by LRRK2 is required for localization to stressed lysosomes.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) such as RAB3IP/Rabin8 and RPGR which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors (GDIs) which inhibit the dissociation of the nucleotide from the GTPase. Activated in response to insulin.

Domain organisation. Switch 1, switch 2 and the interswitch regions are characteristic of Rab GTPases and mediate the interactions with Rab downstream effectors. The switch regions undergo conformational changes upon nucleotide binding which drives interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

Similarity. Belongs to the small GTPase superfamily. Rab family.

Isoforms (2)

UniProt ID	Names	Canonical?
P61006-1	1	yes
P61006-2	2

RefSeq proteins (1): NP_005361* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR050305	Small_GTPase_Rab	Family

Pfam: PF00071

Enzyme classification (BRENDA):

• EC 3.6.5.2 — small monomeric GTPase (BRENDA: 49 organisms, 138 substrates, 55 inhibitors, 5 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	—	0

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (54 total): binding site 19, strand 8, helix 7, mutagenesis site 5, modified residue 4, turn 4, short sequence motif 2, chain 1, propeptide 1, lipid moiety-binding region 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
4LHW	X-RAY DIFFRACTION	1.55
6SQ2	X-RAY DIFFRACTION	1.68
6WHE	X-RAY DIFFRACTION	1.73
6RIR	X-RAY DIFFRACTION	1.77
9M0O	X-RAY DIFFRACTION	1.83
7LWB	X-RAY DIFFRACTION	1.9
6ZSI	X-RAY DIFFRACTION	1.91
9IKQ	X-RAY DIFFRACTION	1.93
4LHV	X-RAY DIFFRACTION	1.95
3QBT	X-RAY DIFFRACTION	2
6ZSJ	X-RAY DIFFRACTION	2
6YX5	X-RAY DIFFRACTION	2.14
7BWT	X-RAY DIFFRACTION	2.3
6STF	X-RAY DIFFRACTION	2.4
3TNF	X-RAY DIFFRACTION	2.5
6STG	X-RAY DIFFRACTION	2.5
5SZI	X-RAY DIFFRACTION	2.85
4LHX	X-RAY DIFFRACTION	3.05
4LHY	X-RAY DIFFRACTION	3.1
4LHZ	X-RAY DIFFRACTION	3.2
4LI0	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61006-F1	85.70	0.70

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (19): 22; 23; 35; 39; 40; 40; 63; 66; 121; 122; 124; 152 …

Post-translational modifications (5): 72, 181, 185, 204, 204

Mutagenesis-validated functional residues (5):

Position	Phenotype
22	loss of interaction with mical1. loss of graf1/arhgap26 and graf2/arhgap10 tubular localization. loss of e-cadherin and
67	probable constitutively active mutant locked in the active gtp-bound form. stimulates interaction with micall1. increase
72	loss of phosphorylation. no effect on the binding of gdp or gtp. localizes primarily to the golgi complex but does not a
72	phosphomimetic mutant. suppresses interaction with gdi1.
72	phosphomimetic mutant. no effect on the binding of gdp or gtp. loss of gdi1, gdi2, chm, chml, rabggta, rabggtb, rab3ip,

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-2565942	Regulation of PLK1 Activity at G2/M Transition
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-5620916	VxPx cargo-targeting to cilium
R-HSA-8854214	TBC/RABGAPs
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 323 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_VESICLE_ORGANIZATION, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, MODULE_45, MORF_UBE2I, GOBP_MEMBRANE_FUSION, MORF_HDAC1, DITTMER_PTHLH_TARGETS_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (20): exocytosis (GO:0006887), obsolete vesicle docking involved in exocytosis (GO:0006904), autophagy (GO:0006914), Golgi organization (GO:0007030), axonogenesis (GO:0007409), regulation of autophagy (GO:0010506), endocytic recycling (GO:0032456), cellular response to insulin stimulus (GO:0032869), regulation of long-term neuronal synaptic plasticity (GO:0048169), Golgi vesicle fusion to target membrane (GO:0048210), regulation of protein transport (GO:0051223), cilium assembly (GO:0060271), protein localization to cilium (GO:0061512), protein localization to plasma membrane (GO:0072659), neurotransmitter receptor transport, endosome to postsynaptic membrane (GO:0098887), neurotransmitter receptor transport to postsynaptic membrane (GO:0098969), vesicle-mediated transport in synapse (GO:0099003), protein transport (GO:0015031), cell projection organization (GO:0030030), regulation of protein localization (GO:0032880)

GO Molecular Function (11): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), small GTPase binding (GO:0031267), myosin V binding (GO:0031489), protein tyrosine kinase binding (GO:1990782), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), protein kinase binding (GO:0019901)

GO Cellular Component (38): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), nucleolus (GO:0005730), lysosome (GO:0005764), endosome (GO:0005768), Golgi apparatus (GO:0005794), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), actin cytoskeleton (GO:0015629), trans-Golgi network transport vesicle (GO:0030140), dendrite (GO:0030425), midbody (GO:0030496), phagocytic vesicle membrane (GO:0030670), trans-Golgi network membrane (GO:0032588), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064), neuronal cell body (GO:0043025), phagocytic vesicle (GO:0045335), recycling endosome membrane (GO:0055038), ciliary membrane (GO:0060170), extracellular exosome (GO:0070062), ciliary base (GO:0097546), non-motile cilium (GO:0097730), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), neuron projection (GO:0043005), synapse (GO:0045202), recycling endosome (GO:0055037)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Rab regulation of trafficking	2
Membrane Trafficking	1
G2/M Transition	1
Assembly of the 9+0 primary cilium	1
Cargo trafficking to the periciliary membrane	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
vesicle-mediated transport	2
intracellular protein localization	2
guanyl ribonucleotide binding	2
bounding membrane of organelle	2
nuclear lumen	2
intracellular membraneless organelle	2
endomembrane system	2
cytoplasm	2
microtubule organizing center	2
cytoskeleton	2
secretion by cell	1
vesicle fusion to plasma membrane	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
organelle organization	1
endomembrane system organization	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
autophagy	1
regulation of catabolic process	1
endosomal transport	1
vesicle-mediated transport to the plasma membrane	1
response to insulin	1
cellular response to peptide hormone stimulus	1
regulation of neuronal synaptic plasticity	1
vesicle fusion	1
Golgi vesicle transport	1
protein transport	1
regulation of transport	1
regulation of establishment of protein localization	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

234 interactions, top by confidence:

A	B	Type	Score
CEP97	CCP110	psi-mi:“MI:2364”(proximity)	0.950
RAB8A	GDI1	psi-mi:“MI:0914”(association)	0.860
EXOC6	EXOC5	psi-mi:“MI:0914”(association)	0.840
GDI1	RAB4A	psi-mi:“MI:0914”(association)	0.820
	RAB8A	psi-mi:“MI:0915”(physical association)	0.820
	RAB8A	psi-mi:“MI:0407”(direct interaction)	0.820
	RAB8A	psi-mi:“MI:0217”(phosphorylation reaction)	0.820
	RAB8A	psi-mi:“MI:0407”(direct interaction)	0.790
	RAB8A	psi-mi:“MI:0217”(phosphorylation reaction)	0.790

BioGRID (306): RAB8A (Affinity Capture-RNA), ODF2 (Two-hybrid), ODF2 (Reconstituted Complex), RAB8A (Affinity Capture-MS), RAB8A (Reconstituted Complex), RAB8A (Affinity Capture-MS), RAB8A (Affinity Capture-MS), ANXA4 (Co-fractionation), GDI1 (Co-fractionation), GDI2 (Co-fractionation), HSD17B10 (Co-fractionation), RAB10 (Co-fractionation), RAB8A (Co-fractionation), RAB8A (Co-fractionation), RAB8A (Co-fractionation)

ESM2 similar proteins: A4FV54, F1PTE3, O24466, O42819, P01123, P11620, P17609, P20790, P20791, P22127, P22128, P24409, P31584, P33723, P34139, P34140, P35280, P35281, P35286, P36410, P51153, P55258, P61006, P61007, P61026, P61027, P61028, P62820, P62821, P62822, P70550, Q05974, Q2HJI8, Q39571, Q4R5P1, Q52NJ2, Q54NU2, Q58DS5, Q5F470, Q5KTJ6

Diamond homologs: A4D1S5, A4FV54, F1PTE3, O04486, O24466, O76173, P01123, P10536, P11620, P16976, P17609, P20790, P20791, P22125, P22128, P28186, P28188, P31584, P33723, P34139, P34140, P35280, P35286, P35294, P36410, P36863, P40392, P51153, P51156, P53994, P55258, P59279, P61006, P61007, P61019, P61028, P61105, P62820, P62821, P62822

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CEP290	“up-regulates activity”	RAB8A	binding
RAB8A	up-regulates	Cilium_assembly
RPGR	“up-regulates activity”	RAB8A	“guanine nucleotide exchange factor”
“BBsome complex”	“up-regulates activity”	RAB8A	binding
STK24	“up-regulates activity”	RAB8A	phosphorylation
MAP3K7	“up-regulates activity”	RAB8A	phosphorylation
LRRK2	“up-regulates activity”	RAB8A	phosphorylation
PINK1	“down-regulates activity”	RAB8A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of pyruvate metabolism	8	41.5×	4e-09
Pyruvate metabolism	5	18.5×	4e-04
RAB GEFs exchange GTP for GDP on RABs	12	13.5×	2e-08
RAB geranylgeranylation	8	12.6×	3e-05
Loss of Nlp from mitotic centrosomes	7	10.1×	4e-04
Loss of proteins required for interphase microtubule organization from the centrosome	7	10.1×	4e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	9.8×	4e-04
AURKA Activation by TPX2	7	9.7×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
Golgi to plasma membrane transport	5	20.4×	1e-03
exocytosis	10	11.0×	3e-05
protein targeting to membrane	5	10.7×	9e-03
vesicle-mediated transport	10	7.0×	1e-03
endocytosis	9	6.2×	3e-03
protein transport	14	4.5×	1e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	11	4.2×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

13 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1123 predictions. Top by Δscore:

Variant	Effect	Δscore
19:16118220:TTTCA:T	acceptor_loss	1.0000
19:16118221:TTCAG:T	acceptor_loss	1.0000
19:16118222:TCAG:T	acceptor_loss	1.0000
19:16118223:CA:C	acceptor_loss	1.0000
19:16118224:A:AC	acceptor_loss	1.0000
19:16118224:A:AG	acceptor_gain	1.0000
19:16118224:AG:A	acceptor_gain	1.0000
19:16118225:G:GA	acceptor_loss	1.0000
19:16118225:G:GG	acceptor_gain	1.0000
19:16118225:GG:G	acceptor_gain	1.0000
19:16118225:GGA:G	acceptor_gain	1.0000
19:16118283:TATGG:T	donor_loss	1.0000
19:16118284:ATGG:A	donor_loss	1.0000
19:16118285:TGG:T	donor_loss	1.0000
19:16118286:GGTAA:G	donor_loss	1.0000
19:16118287:GTA:G	donor_loss	1.0000
19:16118288:T:G	donor_loss	1.0000
19:16121745:TTTA:T	acceptor_loss	1.0000
19:16121746:TTA:T	acceptor_loss	1.0000
19:16121747:TA:T	acceptor_loss	1.0000
19:16121748:A:AC	acceptor_loss	1.0000
19:16121748:A:AG	acceptor_gain	1.0000
19:16121748:AG:A	acceptor_gain	1.0000
19:16121748:AGG:A	acceptor_gain	1.0000
19:16121749:G:GG	acceptor_gain	1.0000
19:16121749:GG:G	acceptor_gain	1.0000
19:16121749:GGG:G	acceptor_gain	1.0000
19:16125463:C:A	acceptor_gain	1.0000
19:16125466:GCA:G	acceptor_loss	1.0000
19:16125468:A:AG	acceptor_gain	1.0000

AlphaMissense

1389 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:16111944:G:A	G15R	1.000
19:16111944:G:C	G15R	1.000
19:16111944:G:T	G15W	1.000
19:16111945:G:A	G15E	1.000
19:16111945:G:T	G15V	1.000
19:16111959:G:A	G20R	1.000
19:16111959:G:C	G20R	1.000
19:16111959:G:T	G20W	1.000
19:16111960:G:A	G20E	1.000
19:16111962:A:C	K21Q	1.000
19:16111966:C:T	T22I	1.000
19:16111998:T:C	F33L	1.000
19:16112000:C:A	F33L	1.000
19:16112000:C:G	F33L	1.000
19:16112020:C:T	T40I	1.000
19:16112025:G:A	G42R	1.000
19:16112025:G:C	G42R	1.000
19:16118226:G:A	G42E	1.000
19:16118234:T:C	F45L	1.000
19:16118236:T:A	F45L	1.000
19:16118236:T:G	F45L	1.000
19:16118277:T:C	L59P	1.000
19:16118283:T:A	I61K	1.000
19:16118285:T:A	W62R	1.000
19:16118285:T:C	W62R	1.000
19:16121750:G:C	W62C	1.000
19:16121750:G:T	W62C	1.000
19:16121751:G:C	D63H	1.000
19:16121752:A:C	D63A	1.000
19:16121752:A:G	D63G	1.000

dbSNP variants (sampled 300 via entrez): RS1000098539 (19:16130983 C>T), RS1000176227 (19:16129707 C>G), RS1000323976 (19:16129829 G>A,C), RS1000359663 (19:16114063 C>A,G,T), RS1000408991 (19:16121194 G>A), RS1000733501 (19:16122390 A>G), RS1000840663 (19:16126067 C>G,T), RS1000902697 (19:16115836 C>G,T), RS1001011335 (19:16120438 G>A,C), RS1001024195 (19:16110671 T>A,C), RS1001062070 (19:16120204 G>A,C), RS1001074634 (19:16110434 A>G), RS1001181915 (19:16119803 G>T), RS1001235546 (19:16119422 C>T), RS1001248393 (19:16116215 G>A)

Disease associations

OMIM: gene MIM:165040 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST004599_146	Mean platelet volume	1.000000e-28
GCST004602_266	Mean corpuscular volume	5.000000e-11
GCST004630_60	Mean corpuscular hemoglobin	3.000000e-15
GCST005993_21	Mean corpuscular hemoglobin	2.000000e-11
GCST90002391_107	Mean corpuscular hemoglobin concentration	3.000000e-13
GCST90002395_406	Mean platelet volume	1.000000e-25
GCST90002402_621	Platelet count	4.000000e-10
GCST90002404_567	Red cell distribution width	7.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004309	platelet count
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067094 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Tretinoin	increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
mitomycin C-DNA adduct	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol S	increases expression	1
LDN 193189	increases expression, affects cotreatment	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Gemcitabine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases response to substance, increases reaction	1
Coumestrol	affects cotreatment, increases expression	1
Curcumin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652222	Binding	Binding affinity to human RAB8A incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6ZY	HeLa M Rab8-DKO	Cancer cell line	Female
CVCL_B2D5	Abcam HeLa RAB8A KO	Cancer cell line	Female
CVCL_B9QU	Abcam A-549 RAB8 KO	Cancer cell line	Male
CVCL_D1U6	Abcam U-87MG RAB8A KO	Cancer cell line	Male
CVCL_TI26	HAP1 RAB8A (-) 1	Cancer cell line	Male
CVCL_TI27	HAP1 RAB8A (-) 2	Cancer cell line	Male
CVCL_TI28	HAP1 RAB8A (-) 3	Cancer cell line	Male
CVCL_TI29	HAP1 RAB8A (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.