Alternative titles; symbolsENDONEXIN, BETA-3Other entities represented in this entry:ENDONEXIN, BETA-3, LONG FORM, INCLUDEDNUCLEAR RECEPTOR-INTERACTING FACTOR 3,...
Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ITGB3BP
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:63,440,769-63,529,394 (from NCBI)
▼ Cloning and Expression
Using a yeast 2-hybrid screen of a B-lymphocyte library for proteins that interact with the cytoplasmic tail of the integrin beta-3 subunit (ITGB3; 173470), Shattil et al. (1995) identified the ITGB3BP cDNA encoding a 111-amino acid polypeptide that they designated beta-3-endonexin. They also identified a longer beta-3-endonexin transcript of 170 amino acids that was identical for the first 111 amino acids, but contained an additional 59 amino acids at the C terminus; the longer form did not interact with the ITGB3 subunit. By Northern blot and RT-PCR analyses, Shattil et al. (1995) detected wide expression of a 1.1-kb ITGB3BP transcript. By immunoblotting of peripheral blood leukocytes, they detected a 13-kD protein.
Li et al. (1999) used a full-length thyroid hormone receptor-alpha subunit (THRA; 190120) for a yeast 2-hybrid screen and identified a third transcript of ITGB3BP, which they called NRIF3. NRIF3 encodes a 177-amino acid protein that shares the first 161 amino acids with the 170-amino acid form identified by Shattil et al. (1995). All 3 forms of ITGB3BP contain a nuclear localization signal (KRKK) and 1 copy of an LxxLL motif that has been implicated in the interaction of a number of putative coactivators with nuclear receptors. Fluorescence microscopy showed that NRIF3 localizes to the cell nucleus, consistent with a putative role as a nuclear receptor coactivator. Li et al. (1999) suggested that their data, together with data from Shattil et al. (1995), indicate a function for ITGB3BP in both cell adhesion and transcriptional regulation.
▼ Gene Function
Shattil et al. (1995) demonstrated that despite conservation in the cytoplasmic tails of most beta-integrin subunits, the short form of ITGB3BP did not interact with integrin subunits other than ITGB3, and a point mutation (S752P) in the ITGB3 cytoplasmic tail that disrupted integrin signaling significantly reduced binding to ITGB3BP.
Li et al. (1999) showed that the 177-amino acid form of ITGB3BP, but not the 111- or 170-amino acid forms, specifically binds to the ligand-binding domain of THRA and the retinoid X-receptor alpha subunit (RXRA; 180245), suggesting a function for ITGB3BP as a coactivator of these nuclear receptors. The binding of ITGB3BP to THRA and RXRA is T3-dependent. ITGB3BP did not potentiate the activity of several other nuclear receptors tested. Li et al. (1999) concluded that the unique C-terminal domain in the 177-amino acid form of ITGB3BP, which they called NCD, is essential for its specific interaction with THRA and RXR. They also concluded that the N-terminal LxxLL motif is not sufficient for receptor interactions, but plays a role in allowing an optimum interaction to occur.
Li et al. (2001) found that the 177-amino acid NRIF3 protein used both its C- and N-terminal receptor-interacting domain to cooperatively interact with THRA or RXR, with the spacing between these domains influencing the affinity of the interactions. Mutagenesis analysis also revealed a central NRIF3-NRIF3 interaction domain. Reporter gene assays showed that the isolated C-terminal domain of NRIF3 activated transcription, while the full-length protein repressed transcription. Both of the shorter NRIF3 isoforms have the repressor domain and coiled-coil dimerization domain, but they lack the C-terminal transcriptional activation domain found in the full-length isoform. Reporter gene activity confirmed their function as transcriptional repressors. Immunofluorescence microscopy localized all 3 NRIF3 isoforms to the nucleus.
Li et al. (2004) found that expression of several splice variants of NRIF3 in human breast cancer cell lines induced rapid and profound apoptosis, with nearly 100% cell death within 24 hours. A 30-amino acid death domain shared by these variants induced apoptosis through a caspase-2 (600639)-mediated pathway that involved mitochondrial membrane permeabilization and did not require other caspases. The cytotoxicity of full-length NRIF3 or the death domain alone appeared to be cell-type specific, as they killed breast cancer or related cells, but not mammalian tumor cells of other tissue origin.
By mass spectrometric analysis of proteins that immunoprecipitated with anti-CENPH (605607) and anti-CENPI (300065) antibodies in HeLa cells, Okada et al. (2006) identified the 177-amino acid isoform of ITGB3BP as a component of the CENPH-CENPI centromeric complex. This isoform, which they called CENPR, has an apparent molecular mass of 20.2 kD by SDS-PAGE.
The International Radiation Hybrid Mapping Consortium mapped the ITGB3BP gene to chromosome 1.