Disease relevance of GABARAP

• In summary, our data suggest that GABARAP acts via a vesicle transport mechanism as a tumor suppressor in breast cancer [1].
• GABARAP mRNA expression and protein expression were significantly down-regulated in invasive ductal and invasive lobular carcinomas compared with normal breast tissue measured by semiquantitative reverse transcription-PCR and immunohistochemistry, respectively [1].
• Sometimes a complete cure was observed in Meth A sarcoma, sarcoma 180, Ehrlich, and MM 46 tumors [2].
• Meth A sarcoma, Colon 26, Ehrlich, sarcoma 180, MM 46, MH 134, B16 melanoma, and Lewis lung tumors transplanted into mice underwent tumor necrosis and regression following a single injection of TNF [2].

High impact information on GABARAP

• GABARAP recognizes and binds the gamma2 subunit of the GABA(A) receptor, interacts with microtubules and the N-ethyl maleimide sensitive factor, and is proposed to function in GABA(A) receptor trafficking and postsynaptic localization [3].
• (2002), in this issue of Neuron, reveal the crystal structure for the GABA(A) receptor binding protein, GABARAP [4].
• The gamma-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics [5].
• In the present work, immunofluorescent staining and green fluorescent protein-tagged receptor subunits showed that GABARAP is associated with and promotes the clustering of GABA(A) receptors in QT-6 quail fibroblasts [5].
• Fine mapping of a linkage region on chromosome 17p13 reveals that GABARAP and DLG4 are associated with vulnerability to nicotine dependence in European-Americans [6].

Chemical compound and disease context of GABARAP

• Twenty-two alkyl lysophospholipid analogs were chemically synthesized, and their antitumor activity against mouse experimental tumors (Sarcoma 180, MM46, P388) was examined [7].

Biological context of GABARAP

• GABAA receptor-associated protein (GABARAP) induces apoptosis by interacting with DEAD (Asp-Glu-Ala-Asp/His) box polypeptide 47 (DDX 47) [8].
• Stable transfection of GABARAP into CAL51 resulted in an increase of gene expression and remarkably influenced the ability of colony formation in soft agar and the growth rate in vitro and, moreover, suppressed the tumorigenicity of the cells in nude mice [1].
• GABARAP interacts with microtubules and the gamma2 subunit of GABA(A) receptor and modulates channel kinetics [9].
• Individual SNP analysis revealed that SNPs rs17710 and rs222843 in GABA(A) receptor-associated protein (GABARAP) exhibited a significant association with at least one age- and gender-adjusted ND measure in the EA sample and rs222843 remained significant with the FTND after correction for multiple testing (P = 0.009) [6].
• We also found an A-A haplotype with a frequency of 8.8% formed by SNPs rs17710 and rs222843 in GABARAP, which revealed significant associations with all three ND measures (P = 0.006, 0.019 and 0.024, for SQ, HSI and FTND, respectively) [6].

Anatomical context of GABARAP

• Guinea-pig and human gec1/GABARAPL1 proteins share 87% identity with GABARAP, which acts as a protein linker between microtubules and the GABA(A) receptor [10].
• Further, co-transfection of GABARAP and DDX47 cDNA into a tumor cell line induces apoptosis [8].
• 1. GABARAP displayed high expression levels in the microcell hybrid CAL/17-1 but only weak expression in CAL51 and other breast cancer cell lines tested [1].
• The gamma-aminobutyric acid receptor type A (GABA(A)) receptor-associated protein (GABARAP) is a member of a growing family of intracellular membrane trafficking and/or fusion proteins and has been implicated in plasma membrane targeting and clustering of GABA(A) receptors [9].
• Deficiency of p38alpha activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis [11].

Associations of GABARAP with chemical compounds

• The gamma-aminobutyric acid, type A (GABA(A)) receptor-associated protein GABARAP was reported to have an important role for movement and sorting of GABA(A) receptor molecules to the postsynaptic membrane [12].
• In addition to phosphatidylethanolamine, in vitro conjugation experiments using synthetic phospholipid liposomes showed that phosphatidylserine is also a target of LC3, GABARAP, and GATE-16 [13].
• In recombinant receptors with fixed stoichiometry, coexpression of GABARAP-enhanced green fluorescent protein (EGFP) fusion protein had no effect on desensitization, deactivation, or diazepam potentiation of GABA-mediated currents [14].
• No appreciable or even adverse stereospecificity was observed in the different sets of experiments where the activity of ET-18-OMe against MM46 tumor cells in vivo or the direct cytotoxicity against human promyelocytic leukemia HL-60 cells in vitro was examined [7].
• Although it has been reported that S100A8/A9 binds to heparan sulfate on cell membranes, the amount of S100A8/A9 bound to MM46 cells was not reduced by heparinase treatment, but was reduced by trypsin treatment [15].

Physical interactions of GABARAP

• Furthermore, using coimmunoprecipitation assays we show that GABARAP interacts with GRIP1 in vivo [16].

Other interactions of GABARAP

• The expression patterns of GABARAPL1, GABARAPL2, and GABARAP in 16 adult tissues showed that they were expressed ubiquitously [17].
• GABARAP and gec1/GABARAPL1 genes encode very similar proteins belonging to a new microtubule-associated protein (MAP) family [18].
• Association of human transferrin receptor with GABARAP [19].
• The binding of GABARAP with NSF, microtubules and gephyrin together with its localization at intracellular membranes suggests a role in GABA(A)R targeting and/or degradation [20].
• Here we show GABARAP associates with the synaptic PDZ domain containing protein GRIP1 [16].

Analytical, diagnostic and therapeutic context of GABARAP

• As an initial step to define the biological role of GABARAP, we searched for binding partners of GABARAP using co-immunoprecipitation coupled with LC-MS/MS analysis [8].
• Quantitative yeast two-hybrid assays were used to identify the interaction domain in the gamma2 subunit for GABARAP binding, and to identify the interaction domain in GABARAP for GABA(A) receptor binding [21].
• In immunoblotting, affinity-purified PA629 (PA629p) recognized GEC1, GABARAP and GATE-16 [22].
• Antibodies raised against GABARAP immunostained neuronal cell bodies as well as axonal and dendritic processes, as visualized by confocal microscopy [23].
• In this study, we combined brain dissection and quantitative real-time reverse transcription polymerase chain reaction to study discriminatively gabarap, gec1/gabarapL1, gate16/gabarapL2, lc3 mRNA distribution in multiple rat brain areas [24].

References