Evidence of MTCBP-1 interaction with the cytoplasmic domain of MT1-MMP: Implications in the autophagy cell index of high-grade glioblastoma.
Progression of astrocytic tumors is, in part, related to their dysregulated autophagy capacity. Recent evidence indicates that upstream autophagy signaling events can be triggered by MT1-MMP, a membrane-bound matrix metalloproteinase that contributes to the invasive phenotype of brain cancer cells. The signaling functions of MT1-MMP require its intracellular domain, and recent identification of MTCBP-1, a cytoplasmic 19 kDa protein involved in the inhibition of MT1-MMP-mediated cell migration, suggests that modulation of MT1-MMP cytoplasmic domain-mediated signaling may affect other carcinogenic processes. Using qPCR and screening of cDNA generated from brain tumor tissues of grades I, II, III, and IV, MT1-MMP gene expression was found to correlate with increased grade of tumors. Inversely, MTCBP-1 expression decreased with increasing grade of brain tumor. Confocal microscopy and fluorescence resonance energy transfer (FRET) analysis revealed that overexpressing a cytoplasmic-deleted MT1-MMP recombinant protein mutant prevented MTCBP-1 recruitment to the intracellular leaf of plasma membrane in U87 glioblastoma cells. The interaction between MTCBP-1 and the 20 amino acids peptide representing the MT1-MMP cytoplasmic domain was confirmed by surface plasmon resonance. Overexpression of a full-length Wt-MT1-MMP triggered acidic autophagy vesicle formation and autophagic puncta formation for green fluorescent microtubule-associated protein 1 light chain 3 (GFP-LC3). Autophagic vesicles and GFP-LC3 puncta formation were abrogated in the presence of MTCBP-1. Our data elucidate a new role for MTCBP-1 regulating the intracellular function of MT1-MMP-mediated autophagy. The inverse correlation between MTCBP-1 and MT1-MMP expression with brain tumor grades could also contribute to the decreased autophagic index observed in high-grade tumors.
['Pratt|Jonathan|J|', 'Iddir|Mustapha|M|', 'Bourgault|Steve|S|', 'Annabi|Borhane|B|']
D001343:Autophagy D001665:Binding Sites D001932:Brain Neoplasms D045744:Cell Line, Tumor D003593:Cytoplasm D049308:Dioxygenases D015972:Gene Expression Regulation, Neoplastic D005909:Glioblastoma D006801:Humans D053511:Matrix Metalloproteinase 14 D011379:Prognosis D017434:Protein Structure, Tertiary
matrix metalloproteinase Brain tumor chemoresistance