title: MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4.
abstract: Murine double minute (MDM2) binding protein (MTBP) has been implicated in cancer progression. Here, we demonstrate one mechanism by which MTBP inhibits cancer metastasis. Overexpression of MTBP in human osteosarcoma cell lines lacking wild-type p53 did not alter primary tumor growth in mice, but significantly inhibited metastases. MTBP downregulation increased the migratory potential of MDM2(-/-)p53(-/-) mouse embryonic fibroblasts, suggesting that MTBP inhibited cell migration independently of the Mdm2-p53 pathway. Co-immunoprecipitation and mass spectrometric analysis identified alpha-actinin-4 (ACTN4) as an MTBP-interacting protein. Endogenous MTBP interacted with and partially colocalized with ACTN4. MTBP overexpression inhibited cell migration and filopodia formation mediated by ACTN4. Increased cell migration by MTBP downregulation was inhibited by concomitant downregulation of ACTN4. MTBP also inhibited ACTN4-mediated F-actin bundling. We furthermore demonstrated that nuclear localization of MTBP was dispensable for inhibiting ACTN4-mediated cell migration and filopodia formation. Thus, MTBP suppresses cell migration, at least partially, by inhibiting ACTN4 function. Our study not only provides a mechanism of metastasis suppression by MTBP, but also suggests MTBP as a potential biomarker for cancer progression.
authors.affiliation: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Agarwal
authors.forename: A S
authors.initials: AS
authors.lastname: Adhikari
authors.forename: S V
authors.initials: SV
authors.lastname: Iyer
authors.forename: K
authors.initials: K
authors.lastname: Hekmatdoost
authors.forename: D R
authors.initials: DR
authors.lastname: Welch
authors.forename: T
authors.initials: T
authors.lastname: Iwakuma
mesh_terms: D000185:Actinin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C111453:ACTN4 protein, human; D000199:Actins; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C485931:MTBP protein, human; D016159:Tumor Suppressor Protein p53; D000185:Actinin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2