Ask about this productRelated genes to: RAB4A antibody
- Gene:
- RAB4A NIH gene
- Name:
- RAB4A, member RAS oncogene family
- Previous symbol:
- RAB4
- Synonyms:
- HRES-1/RAB4
- Chromosome:
- 1q42.13
- Locus Type:
- gene with protein product
- Date approved:
- 1989-09-11
- Date modifiied:
- 2016-10-05
Related products to: RAB4A antibody
Related articles to: RAB4A antibody
- Extracellular vesicles (EVs) secreted by cancer cells actively modulate the tumor microenvironment, thereby promoting cancer progression. Transforming growth factor-β (TGF-β) signaling has been implicated in the regulation of EV biogenesis, yet the molecular mechanisms underlying this process have only recently begun to emerge. In this study, we investigated TGF-β-responsive mediators that regulate EV release in lung, breast, and ovarian carcinoma cells by modulating the expression and activity of genes associated with EV biogenesis, including components of the ESCRT machinery, tetraspanins, and Rab GTPases. We found that TGF-β selectively enhances the mRNA expression of PDCD6IP (ALIX), CD81, ARF6, and RAB4A in a cell type-specific manner. R-SMAD silencing had clear negative effects on the regulation of ALIX or RAB4A, whereas AKT kinase inhibition suppressed the induction of ALIX and CD81. Additionally, TGF-β stimulation increased ALIX S-palmitoylation, consistent with enhanced ALIX-TSG101 complex formation on vesicular membranes. However, knockdown of ALIX or CD81 did not impair TGF-β-induced EV secretion. On the contrary, TGF-β-induced upregulation of RAB4A expression is functionally unique because RAB4A facilitates fast endosomal recycling, a process that limits EV release. Accordingly, silencing RAB4A significantly increased the fusion of multivesicular bodies with the plasma membrane followed by EV secretion, suggesting that TGF-β-induced RAB4A acts as a negative feedback regulator of EV release. Our findings reveal a novel mechanism by which RAB4A modulates TGF-β-driven EV production by cancer cells. - Source: PubMed
Publication date: 2026/03/30
Rodrigues-Junior Dorival MendesDoumani Maria AnastasiaFu Haovan den Bor JelleIdevall-Hagren OlofMoustakas Aristidis - Large-conductance Ca-activated potassium (BK) channels are widely expressed across human tissues and play fundamental roles in the regulation of diverse cellular processes. Dysregulation of BK channel expression or activity has been implicated in multiple pathological conditions, including cancer, where BK channel overexpression is associated with enhanced tumor cell proliferation and altered cellular dynamics. In this study, we present an integrative computational framework to identify, structurally characterize, and rationally target BK channel-associated protein-protein interactions (PPI) in breast cancer. RNA-seq differential expression analysis revealed significant overexpression of KCNMA1 in estrogen-sensitive breast cancer cells, supporting a central role for BK channels in tumor-associated phenotypes. By integrating transcriptomic data with curated interaction databases and PPI prediction methods, we constructed a breast cancer-specific interaction network centered on BK and identified ACTG2, LINGO1, and RAB4A as high-confidence interaction partners. Structural modeling and coarse-grained molecular dynamics simulations revealed stable, partner-specific interaction interfaces between BK and each interactor, identifying key residues governing complex formation. Building on these results, we present the first computational structural model of the BK-LINGO1 complex, which reveals a predominantly hydrophobic transmembrane interface consistent with the established role of LINGO1 as a regulatory accessory subunit. Leveraging this PPI interface, we designed peptide-based modulators using a structure-guided approach and identified peptide variants with enhanced conformational stability and favorable binding energetics. Overall, our work establishes a robust computational framework for mapping BK channel protein-protein interactions in breast cancer and demonstrates the feasibility of targeting these interactions through rational peptide design, opening new opportunities for the selective modulation of BK channel function in cancer. - Source: PubMed
Publication date: 2026/03/17
González-Avendaño MarielaRosales-Rojas RobertoVergara-Jaque Ariela - Platelet α-granules are lysosome-related organelles produced in megakaryocytes, the platelet precursor cells. The biogenesis of α-granules is incompletely understood but depends on common endosomal pathways. Here, we discovered GRIPAP1, a partially characterized ubiquitous protein, as a new component of the α-granule biogenesis machinery. GRIPAP1-deficient megakaryocytes showed a significant decrease of α-granule numbers and overall cargo levels. In WT megakaryocytes, fibrinogen taken up by endocytosis and newly synthesized PF4 trafficked through GRIPAP1-labeled compartments en route to α-granules. GRIPAP1 localized to endosome subdomains decorated by Rab4a and Stx12, known players in α-granule biogenesis. GRIPAP1 bound GTP-loaded Rab4a, a key interaction for GRIPAP1 recruitment to membranes. Biochemically, GRIPAP1 behaved as an elongated homodimer akin to membrane tethering factors. Consistently, artificial mislocalization of GRIPAP1 to the mitochondria was sufficient to recruit Rab4a compartments containing internalized transferrin and newly synthesized PF4 to mitochondria. Together, the data advance understanding of endosomal transport, the biogenesis of α-granules, and likely other endo-lysosomal organelles. - Source: PubMed
Publication date: 2026/02/03
Ambrosio Andrea LFebvre Hallie PSchusler Gabrielle HDi Pietro Santiago M - Alzheimer's disease (AD) is characterized by widespread molecular dysregulation, with the APOEe4 allele recognized as its strongest genetic risk factor. However, the mechanisms by which APOEe4 drives distinct molecular changes - whether by exacerbating pathology or triggering compensatory responses - remain incompletely understood. We generated and analyzed proteomic, epigenetic, and genetic data from post-mortem dorsolateral prefrontal cortex samples of a uniquely APOEe4-enriched subset of the Religious Orders Study and Memory and Aging Project (ROSMAP). Specifically, we generated DIA LC-MS proteomic data (n = 302), analyzed previously generated DNA methylation profiles from our group (n = 310), and used published whole-genome sequencing data (n = 254) to compute polygenic risk scores (PRS). In this cohort, 69% (n = 214) were APOEe4 carriers, and 19.6% (n = 42) of them showed no pathological evidence of AD based on NIA-Reagan criteria, enabling identification of APOEe4-related risk and resilience mechanisms. In the absence of AD, APOEe4 carriers exhibited lower levels of 27 proteins, suggesting early synaptic (e.g., VAMP1, SYN3, CASKIN1) and metabolic (e.g., GLUD1, PI4KA) vulnerability. By contrast, APOEe4 carriers with AD displayed marked upregulation of inflammatory and proteostatic proteins (e.g., GNAO1, AHNAK, FGG, HEBP1, APEX1, RAB4A, SLC12A5, LRP1, BAG6) and hypermethylation of cg06329447 in ELAVL4. Network analyses highlighted convergent disruptions in synaptic transmission, metabolism, and proteostasis - key pathways altered in APOEe4-associated AD. Mediation analyses identified GRIPAP1 and GSTK1 as top protein mediators (accounting for ~26-33% of APOEe4's effect), with VAMP1, CASKIN1, DPP3, SYN3, and FGG each contributing ~9-15%. ELAVL4 hypermethylation also mediated ~12% of the APOEe4 effect, linking epigenetic dysregulation to disease risk. To assess whether the identified proteins reflected broader genetic risk for AD or were specific to APOEe4, we calculated PRS both excluding and including the APOE genomic region. While the non-APOE PRS showed no association with identified molecular markers, the APOE-inclusive PRS was significantly associated with eight AD-related proteins in carriers, indicating they are not explained by polygenic risk outside of APOE. Finally, predictive modeling stratified by APOEe4 status revealed that in non-carriers, PRS most effectively classified AD (AUC = 0.73), whereas in carriers, proteomic and epigenetic markers outperformed PRS (AUC up to 0.74). Together, these findings demonstrate that APOEe4 confers AD risk through early synaptic and metabolic disruptions and later-stage inflammatory and epigenetic changes, laying the groundwork for genotype-tailored biomarker development and therapeutic strategies. - Source: PubMed
Publication date: 2025/10/16
Markov YaroslavPriyanka AhanaXu LeqiWang WeiweiThrush-Evensen KyraGonzalez JohnBorrus DanielKasamoto JessicaSehgal RaghavZou GraceFraij JenelCarlyle Becky CHorvath SteveBennett David AZhao Hongyuvan Dyck Christopher HLam TuKiet TLevine Morgan EHiggins-Chen Albert T - Rab4A, a small GTPase overexpressed in T cells of patients with systemic lupus erythematosus (SLE), has been shown to activate mechanistic target of rapamycin (mTOR) signaling, which promotes proinflammatory T cell development and predisposes to nephritis in SLE. In this study, we demonstrate that Rab4A facilitates the endocytic recycling and surface expression of CD38, which, in turn, triggers NAD depletion, activates mTOR complex 1, and suppresses interleukin-2 (IL-2) production in CD4 T cells. Rab4A-driven CD38-mediated NAD depletion elicits the accumulation of nicotinamide and ADP-ribose and secondary depletion of cyclic ADP-ribose. Surprisingly, rapamycin further enhanced CD38 expression and reduced IL-2 secretion, suggesting that IL-2 depletion is mTOR-independent. Alternatively, Rab4A-driven upregulation of CD38 promoted STAT3 expression and its acetylation, as well as FOXO1 expression, which underlies IL-2 depletion in CD4 T cells. These findings reveal a novel Rab4A-driven CD38 signaling axis that links receptor trafficking to proinflammatory metabolic pathways, providing new targets for treatment in SLE. - Source: PubMed
Publication date: 2025/06/12
Park Joy SKrakko DanielNolan JessicaWyman BrandonSadeghzadeh MahsaPerl Andras