Disease relevance of BAIAP2

• Five proteins including IRSp53 and missing in metastasis (MIM) protein share this unique domain and are highly conserved in vertebrates [1].
• In addition, IRSp53/Eps8 complex formation as determined by fluorescent resonance energy transfer analysis, occurs at the leading edge of motile cells, and the motility and invasiveness of HT1080 fibrosarcoma cells are suppressed by inhibiting complex formation [2].
• We found that although Salmonella infection strongly promotes the formation of an IRSp53/WAVE2 complex, IRSp53 is not necessary for bacterial internalization [3].
• The biological roles of BAP2 propeptide and mature peptide have been investigated by heterologous expression of the proprotein in Escherichia coli, and by tests of its fungistatic activity and that of the fully processed form in vitro [4].

High impact information on BAIAP2

• Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism [5].
• Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac [6].
• Moreover, activated Cdc42 but not Rac weakened the association between WAVE2 and IRSp53 [6].
• We found that the knockdown of IRSp53 by RNA interference decreased lamellipodium formation without a decrease in the amount of WAVE2 complex [6].
• Mutagenesis of conserved basic residues at the extreme ends of the dimer abrogated actin bundling in vitro and filopodia formation in vivo, demonstrating that IMD-mediated actin bundling is required for IRSp53-induced filopodia formation [7].

Biological context of BAIAP2

• Using its intracellular carboxyl terminus as "bait" in a yeast two-hybrid system, we isolated a cDNA clone named BAIAP2 whose nucleotide sequence would encode a 521-amino acid protein showing significant homology to a 58/53-kDa substrate of insulin-receptor kinase in the hamster [8].
• In vitro binding assays confirmed that a proline-rich cytoplasmic fragment of BAI1 interacted with the Src homology 3 (SH3) domain of BAIAP2 [8].
• IRS-58 is a brain-enriched protein comprising at least four protein-protein interaction sites: a Cdc42Hs binding site, an Src homology (SH)3-binding site, an SH3 domain, and a tryptophan, tyrptophan (WW)-binding domain [9].
• Here, we search for other binding partners for the IRSp53 SH3 domain and identify Eps8 as the major binding protein in fibroblasts and various cancer cell lines [2].
• Our analysis of IRSp58/53 mRNA suggests that within rat brain there is one coding region for IRSp58 and IRSp53; we find no evidence of alternative splicing [10].

Anatomical context of BAIAP2

• As a protein partner of BAI1, BAIAP2 may represent an important link between membrane and cytoskeleton in the process of neuronal growth [8].
• Mena and IRSp53 act synergistically to promote filopodia formation [11].
• In N1E-115 cells IRS-58 induces neurite outgrowth with high complexity [9].
• In Swiss 3T3 cells and N1E-115 cells, IRS-58 colocalizes with F-actin in clusters and filopodia [9].
• Expression of IRS-58 in Swiss 3T3 cells leads to reorganization of the filamentous (F)-actin cytoskeleton, involving loss of stress fibers and formation of filopodia and clusters [9].

Associations of BAIAP2 with chemical compounds

• IRSp53 and BAIAP2 have independently been isolated as a 58/53-kDa protein tyrosine phosphorylated in response to insulin and a BAI1-binding protein, respectively [12].
• A proline-rich region near the polyglutamine tract of the DRPLA protein and the SH3 domain of IRSp53 were involved in the binding [13].

Physical interactions of BAIAP2

• Interestingly, IRSp53 coprecipitates with shank1 from transfected HEK cells in a small G-protein-regulated manner [14].
• MALS is a binding partner of IRSp53 at cell-cell contacts [15].

Regulatory relationships of BAIAP2

• Furthermore, we found that filopodium-inducing IMD activity in the full-length IRSp53 was regulated by active Cdc42 and Rac1 [1].
• IRSp53 also binds to the activated form of the small G-protein cdc42 [14].

Other interactions of BAIAP2

• The insulin receptor substrate IRSp53 links postsynaptic shank1 to the small G-protein cdc42 [14].
• Binding of the DRPLA protein to IRSp53 was ascertained by co-immunoprecipitation with antibodies and also by co-localization in perinuclear oval dots in cells expressing engineered constructs [13].
• Using affinity chromatography, we have identified Mena, an Ena/VASP family member, as interacting with the SH3 domain of IRSp53 [11].
• Therefore, IRSp53 optimizes the activity of the WAVE2 complex in the presence of activated Rac and PIP(3) [6].
• In HEK cells, overexpressed IRSp53 induces filopodia and targets PSD-95 into these processes [16].

Analytical, diagnostic and therapeutic context of BAIAP2

• As the expression profile of BAIAP2 examined by Northern blot analysis was almost identical to that of BAI1, BAIAP2 appears to be active mainly in neurons [8].
• Immunocytochemistry showed the colocalization of IRSp53 and MALS at cell-cell contacts [15].

References