title: Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein.
abstract: AAA domain containing 3A (ATAD3A) is an integral mitochondrial membrane protein with unknown function, although we now show that high-level expression is associated with poor survival in breast cancer patients. Using a mass spectrometry approach we have demonstrated that ATAD3A interacts with the WASF3 metastasis-promoting protein. Knockdown of ATAD3A leads to decreased WASF3 protein levels in breast and colon cancer cells. Silencing ATAD3A also results in loss of both cell anchorage-independent growth and invasion and suppression of tumor growth and metastasis in vivo using immuno-compromised mice. HSP70 is responsible for stabilizing WASF3 in the cytoplasm, but inactivation of HSP70 does not lead to the loss of WASF3 stability at the mitochondrial membrane, where presumably it is protected through its interaction with ATAD3A. In response to endoplasmic reticulum (ER) stress, increases in the GRP78 protein level leads to increased WASF3 protein levels. We also show that ATAD3A was present in a WASF3-GRP78 complex, and suppression of GRP78 led to destabilization of WASF3 at the mitochondrial membrane, which was ATAD3A dependent. Furthermore, ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability. Proteolysis experiments using isolated mitochondria demonstrates the presence of the N-terminal end of WASF3 within the mitochondria, which is the interaction site with the N-terminal end of ATAD3A. It appears, therefore, that stabilization of WASF3 function occurs through its interaction with ATAD3A and GRP78, which may provide a bridge between the ER and mitochondria, allowing communication between the two organelles. These findings also suggest that pharmacologic inhibition of ATAD3A could be an effective therapeutic strategy to treat human cancer.
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.|Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: X
authors.initials: X
authors.lastname: Ren
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.|Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shull
authors.affiliation: Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000235:genetics; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C549686:ATAD3A protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities
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