title: Evidence of MTCBP-1 interaction with the cytoplasmic domain of MT1-MMP: Implications in the autophagy cell index of high-grade glioblastoma.
abstract: 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.
authors: Laboratoire d'Oncologie Moléculaire, Centre de recherche Biomed, Quebec, Canada.
authors: Jonathan
authors: J
authors: Pratt
authors: Laboratoire d'Oncologie Moléculaire, Centre de recherche Biomed, Quebec, Canada.
authors: Mustapha
authors: M
authors: Iddir
authors: Centre de recherche Pharmaqam, Département de Chimie, Université du Québec à Montréal, Quebec, Canada.
authors: Steve
authors: S
authors: Bourgault
authors: Laboratoire d'Oncologie Moléculaire, Centre de recherche Biomed, Quebec, Canada.
authors: Borhane
authors: B
authors: Annabi
mesh_terms: D001343:Autophagy; D001665:Binding Sites; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D017434:Protein Structure, Tertiary
chemical_list: C484693:ADI1 protein, human; D049308:Dioxygenases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Brain tumor; chemoresistance; matrix metalloproteinase