Affinage

RABGGTA

Geranylgeranyl transferase type-2 subunit alpha · UniProt Q92696

Length
567 aa
Mass
65.1 kDa
Annotated
2026-06-10
20 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RABGGTA encodes the alpha-subunit of Rab geranylgeranyl transferase (RabGGTase/GGTase II), the enzyme that catalyzes geranylgeranylation of Rab GTPases, a lipid modification required for their membrane association and function (PMID:10737774). Loss-of-function established by the gunmetal mouse splice-acceptor mutation reduces RabGGTase activity and decreases geranylgeranylation and membrane association of Rab27, producing thrombocytopenia, prolonged bleeding, and reduced platelet granule contents (PMID:10737774). Through prenylation of distinct Rab substrates, RABGGTA supports tissue-specific signaling: in liver it geranylgeranylates RAB14 to permit mTORC2 assembly and AKT(Ser473) phosphorylation in hepatic insulin signaling (PMID:34995578), while in skeletal muscle it acts via RAB8A to enable insulin-stimulated GLUT4 translocation and glucose uptake without affecting AKT phosphorylation (PMID:35961942). RABGGTA is also required for cancer cell proliferation, mediating the anti-proliferative action of zoledronic acid (PMID:27462771), and is essential for neuronal survival in vivo (PMID:40847019); across these settings the prenylation-dependent phenotypes are rescued by geranylgeranyl pyrophosphate supplementation (PMID:27462771, PMID:34995578).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1997 Medium

    Resolved whether RABGGTA, despite tight physical linkage to TGM1, shares its differentiation-dependent regulation, establishing RABGGTA as an independently regulated, housekeeping-like gene.

    Evidence RT-PCR of RABGGTA and TGM1 in keratinocytes under multiple differentiation stimuli plus genomic structure characterization

    PMID:9196026

    Open questions at the time
    • Does not define RABGGTA protein function
    • Promoter/regulatory elements driving RABGGTA expression not mapped
  2. 2000 High

    Established that RABGGTA encodes the alpha-subunit of RabGGTase and that its loss reduces Rab27 geranylgeranylation and membrane association, linking the enzyme directly to platelet biogenesis.

    Evidence Positional cloning of the gunmetal mouse splice mutation, platelet GGTase activity assay, and Rab27 geranylgeranylation/membrane-association assay

    PMID:10737774

    Open questions at the time
    • Other Rab substrates not enumerated
    • Structural basis of substrate selection not addressed
    • Residual ~4-fold-reduced activity may mask null phenotype
  3. 2000 Medium

    Tested whether human platelet storage pool deficiencies arise from RABGGTA coding mutations, finding only polymorphisms and excluding RABGGTA coding lesions as the cause in these patients.

    Evidence Sequencing of the complete RABGGTA coding region and 5'-UTR in SPD patients and controls

    PMID:11136552

    Open questions at the time
    • Regulatory/non-coding variants not excluded
    • Negative result does not establish a positive disease mechanism
  4. 2016 Medium

    Connected RABGGTA-mediated Rab geranylgeranylation to cancer cell proliferation and identified it as the effector of zoledronic acid's anti-cancer action.

    Evidence siRNA knockdown of RABGGTA in GBM and breast cancer lines, proliferation assay, and GGPP rescue

    PMID:27462771

    Open questions at the time
    • Specific Rab substrate(s) mediating proliferation not identified
    • Single lab, two cell-line types
  5. 2022 High

    Defined a tissue-specific substrate axis in liver, showing RABGGTA geranylgeranylates RAB14 to enable mTORC2 assembly and AKT phosphorylation in hepatic insulin signaling.

    Evidence AAV8 liver-specific Rabggta knockdown in vivo, siRNA screen identifying RAB14, geranylgeranylation/AKT/mTORC2 assays, and GGPP rescue

    PMID:34995578

    Open questions at the time
    • Direct enzyme–RAB14 binding not structurally resolved
    • How RAB14 prenylation regulates mTORC2 assembly mechanistically unclear
  6. 2022 High

    Showed the relevant Rab substrate differs by tissue, with RABGGTA acting through RAB8A in skeletal muscle to control GLUT4 translocation independent of AKT.

    Evidence AAV9 muscle-specific RABGGTA knockdown in vivo, RAB8A geranylgeranylation-site mutagenesis, GLUT4 translocation and glucose uptake assays

    PMID:35961942

    Open questions at the time
    • Mechanism coupling RAB8A prenylation to GLUT4 vesicle trafficking not detailed
    • Why AKT signaling is spared in muscle but not liver unexplained
  7. 2025 Medium

    Established RABGGTA as essential for neuronal survival in vivo, extending Rab geranylgeranylation requirement to neuronal viability.

    Evidence In vivo pooled CRISPR screen (CrAAVe-seq) in mouse brain with neuronal survival validation

    PMID:40847019

    Open questions at the time
    • Rab substrate(s) underlying neuronal survival not identified
    • Cell-death pathway engaged upon depletion uncharacterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RABGGTA selects among different Rab substrates to produce tissue-specific signaling outcomes and what its physiological role is in human disease.
  • No structural model of substrate recognition in the corpus
  • No causative human disease mutation identified
  • Determinants of tissue-specific Rab substrate usage unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 1
Partners
RAB14RAB27RAB8A
Complex memberships
Rab geranylgeranyl transferase (GGTase II)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 A G→A substitution mutation in a splice acceptor site within Rabggta (encoding the alpha-subunit of Rab geranylgeranyl transferase, RabGGTase/GGTase II) in the gunmetal mouse causes skipping of exon 1 and loss of start codon, reducing Rabggta protein and RabGGTase activity ~4-fold in platelets; this leads to significantly decreased geranylgeranylation and membrane association of Rab27, resulting in thrombocytopenia, prolonged bleeding, and reduced platelet granule contents. Positional cloning, splice-site mutation characterization, biochemical measurement of GGTase activity in platelets, and geranylgeranylation/membrane-association assay of Rab27 in mutant vs. wild-type platelets Proceedings of the National Academy of Sciences of the United States of America High 10737774
1997 The human RABGGTA gene (encoding the alpha-subunit of Rab geranylgeranyl transferase) is positioned in a tandem head-to-tail arrangement with the TGM1 gene, with the RABGGTA polyadenylation signal located only 2.3 kbp upstream of the TGM1 cap site; however, RT-PCR analysis under multiple differentiation conditions showed that RABGGTA expression in epidermal keratinocytes is unaffected by calcium concentration, retinoic acid, vitamin D3, or TPA, while TGM1 expression is strongly affected by these same stimuli—demonstrating the two genes are not functionally co-regulated despite close physical linkage. RT-PCR of RABGGTA and TGM1 expression in normal human epidermal keratinocytes under various differentiation conditions; genomic structure characterization Biochemical and biophysical research communications Medium 9196026
2000 The 5'-UTR structure of the human RABGGTA gene shares organizational features with the mouse Rabggta gene (exon alpha upstream of intron alpha), and features of the 5'-UTR are consistent with a housekeeping gene; sequencing of the entire coding region in patients with platelet storage pool deficiencies (alpha-SPD, delta-SPD, gray platelet syndrome) identified several polymorphisms but no obvious disease-causing mutations, indicating these patients do not have RABGGTA coding mutations. Sequencing of complete coding region and 5'-UTR of RABGGTA in patients with platelet storage pool deficiencies and normal individuals; comparative genomic analysis Molecular genetics and metabolism Medium 11136552
2016 Knockdown of RABGGTA (encoding a subunit of RabGGTase/GGTase II) in human cancer cell lines induces an anti-proliferative effect similar to zoledronic acid, and this effect is rescued by geranylgeranyl diphosphate (GGPP) supplementation, demonstrating that RABGGTA-mediated geranylgeranylation of Rab proteins mediates the anti-cancer mechanism of zoledronic acid. siRNA knockdown of RABGGTA in cancer cell lines (GBM, breast cancer); cell proliferation assay; GGPP rescue experiment Oncotarget Medium 27462771
2022 AAV8-mediated knockdown of liver RABGGTA (the alpha-subunit of GGTase II) in vivo causes systemic glucose metabolism disorders; pharmacological and genetic inhibition of GGTase II disrupts hepatic insulin signaling by blocking geranylgeranylation of RAB14, which inhibits AKT (Ser473) phosphorylation and impairs mTORC2 complex assembly; GGPP supplementation rescues the defect. AAV8-mediated in vivo liver-specific Rabggta knockdown; siRNA screening to identify RAB14; geranylgeranylation assay; AKT phosphorylation assay; mTORC2 assembly assay; GGPP rescue in vitro and in vivo Metabolism: clinical and experimental High 34995578
2022 AAV9-mediated knockdown of RABGGTA in skeletal muscle impairs glucose disposal in vivo without disrupting insulin signaling (AKT phosphorylation unaffected); geranylgeranylation deficiency of RAB8A (a GGTase II substrate) specifically inhibits insulin-stimulated GLUT4 translocation and glucose uptake in skeletal muscle cells, identifying RAB8A as the relevant Rab substrate downstream of RABGGTA in this tissue. AAV9-mediated in vivo skeletal muscle RABGGTA knockdown; glucose uptake assay; RAB8A geranylgeranylation-site mutation; GLUT4 translocation assay; AKT phosphorylation assay Journal of cachexia, sarcopenia and muscle High 35961942
2025 In vivo CRISPR screening using CrAAVe-seq in mouse neurons validated Rabggta as an essential gene for neuronal survival; sgRNA-mediated depletion of Rabggta led to loss of neurons, establishing a required role for Rab geranylgeranylation in neuronal viability. In vivo pooled CRISPR screening (CrAAVe-seq) with AAV-delivered sgRNA libraries in mouse brains; validated by neuronal survival assay Nature neuroscience Medium 40847019

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Human genetics 227 18172690
2000 Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis. Proceedings of the National Academy of Sciences of the United States of America 131 10737774
2016 Gene signatures associated with adaptive humoral immunity following seasonal influenza A/H1N1 vaccination. Genes and immunity 21 27534615
2016 Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells. Oncotarget 20 27462771
2025 CRISPR screening by AAV episome-sequencing (CrAAVe-seq): a scalable cell-type-specific in vivo platform uncovers neuronal essential genes. Nature neuroscience 15 40847019
2017 Mapping the in vitro interactome of cardiac sodium (Na+ )-calcium (Ca2+ ) exchanger 1 (NCX1). Proteomics 15 28755400
2022 Triphenyltin exposure induced abnormal morphological colouration in adult male guppies (Poecilia reticulata). Ecotoxicology and environmental safety 13 35905627
2018 Assessment of Protein Prenylation Pathway in Multiple Sclerosis Patients. Journal of molecular neuroscience : MN 10 29574663
2024 Sequential window acquisition of all theoretical mass spectra (SWATH-MS) as an emerging proteomics approach for the discovery of dark-cutting beef biomarkers. Meat science 8 39096797
2020 Proteome alterations associated with the oleic acid and cis-9, trans-11 conjugated linoleic acid content in bovine skeletal muscle. Journal of proteomics 8 32335295
2022 Mevalonate pathway orchestrates insulin signaling via RAB14 geranylgeranylation-mediated phosphorylation of AKT to regulate hepatic glucose metabolism. Metabolism: clinical and experimental 7 34995578
1997 The genes encoding geranylgeranyl transferase alpha-subunit and transglutaminase 1 are very closely linked but not functionally related in terminally differentiating keratinocytes. Biochemical and biophysical research communications 6 9196026
2022 Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity. Journal of cachexia, sarcopenia and muscle 5 35961942
2013 Genetic characterization and in vivo image analysis of novel zebrafish Danio rerio pigment mutants. Journal of fish biology 5 23639161
2000 5'-UTR structural organization, transcript expression, and mutational analysis of the human Rab geranylgeranyl transferase alpha-subunit (RABGGTA) gene. Molecular genetics and metabolism 5 11136552
2023 Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis. Brain sciences 2 38002490
2025 Significant upregulation of prenyltransferase-related genes in neuromyelitis optica: Diagnostic potential and clinical correlations. Multiple sclerosis and related disorders 1 40712510
2023 Sex-based Dysregulation of Inflammation-related Genes in Periodontitis. International journal of molecular and cellular medicine 1 38751653
2026 CpG Methylation of Protein Prenyltransferase Genes FNTA, FNTB, PGGT1B and RABGGTA in Cancer Cell Lines. Epigenomes 0 41892366
2026 Machine learning identifies molecular targets of Di (2-ethylhexyl) phthalate in pulmonary arterial hypertension. Frontiers in bioinformatics 0 41938339

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