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DNAJB1 negatively regulates MIG6 to promote epidermal growth factor receptor signaling

 Soo-Yeon Park  ;  Hyo-Kyoung Choi  ;  Jae Sung Seo  ;  Jung-Yoon Yoo  ;  Jae-Wook Jeong  ;  Youngsok Choi  ;  Kyung-Chul Choi  ;  Ho-Geun Yoon 
 Biochimica et Biophysica Acta - Molecular Cell Research, Vol.1853(10 Pt A) : 2722-2730, 2015 
Journal Title
 Biochimica et Biophysica Acta - Molecular Cell Research 
Issue Date
Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism* ; Cell Line, Tumor ; Gene Knockdown Techniques ; HSP40 Heat-Shock Proteins/genetics ; HSP40 Heat-Shock Proteins/metabolism* ; Humans ; Protein Binding ; Receptor, Epidermal Growth Factor/genetics ; Receptor, Epidermal Growth Factor/metabolism* ; Signal Transduction/physiology* ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism* ; Ubiquitination/physiology*
DNAJB1 ; EGFR ; Gefitinib ; Lung cancer ; MIG6
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.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Soo Yeon(박수연) ORCID logo https://orcid.org/0000-0003-3743-9554
Seo, Jae Sung(서재성)
Yoo, Jung Yoon(유정윤) ORCID logo https://orcid.org/0000-0001-9366-3863
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
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