title: DNAJB1 negatively regulates MIG6 to promote epidermal growth factor receptor signaling.
abstract: Mitogen-inducible gene 6 (MIG6) is a tumor suppressor implicated in the development of human cancers; however, the regulatory mechanisms of MIG6 remain unknown. Here, using a yeast two-hybrid screen, we identified DnaJ homolog subfamily B member I (DNAJB1) as a novel MIG6-interacting protein. We found that DNAJB1 binds to and decreases MIG6 protein, but not mRNA, levels. DNAJB1 overexpression dosage-dependently decreased MIG6 protein levels. Conversely, DNAJB1 knockdown increased MIG6 protein levels. DNAJB1 destabilizes MIG6 by enhancing K48-linked ubiquitination of MIG6. However, knocking-down of DNAJB1 reduced the ubiquitination of MIG6. DNAJB1 positively regulates the epidermal growth factor receptors (EGFR) signaling pathway via destabilization of MIG6; however, DNAJB1 knockdown diminishes activation of EGFR signaling as well as elevation of MIG6. Importantly, the increased levels of MIG6 by DNAJB1 knockdown greatly enhanced the gefitinib sensitivity in A549 cells. Thus, our study provides a new molecular mechanism to regulate EGFR signaling through modulation of MIG6 by DNAJB1 as a negative regulator.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, Republic of Korea.
authors.forename: Hyo-Kyoung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University College of Human Medicine, MI, USA.
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University College of Human Medicine, MI, USA.
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Fertility Center of CHA General Hospital, CHA Research Institute, CHA University, Seoul, Republic of Korea.
authors.forename: Youngsok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: choikc75@amc.seoul.ac.kr.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: yhgeun@yuhs.ac.
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494647:DNAJB1 protein, human; C484017:ERRFI1 protein, human; D050956:HSP40 Heat-Shock Proteins; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: DNAJB1; EGFR; Gefitinib; Lung cancer; MIG6