title: Smad7 Modulates Epidermal Growth Factor Receptor Turnover through Sequestration of c-Cbl.
abstract: Epidermal growth factor (EGF) regulates various cellular events, including proliferation, differentiation, migration, and tumorigenesis. For the maintenance of homeostasis, EGF signaling should be tightly regulated to prevent the aberrant activation. Smad7 has been known as inhibitory Smad that blocks the signal transduction of transforming growth factor β. In the process of cell proliferation or transformation, Smad7 has been shown the opposite activities as a promoter or suppressor depending on cell types or microenvironments. We found that the overexpression of Smad7 in human HaCaT keratinocyte cells and mouse skin tissues elevated EGF receptor (EGFR) activity by impairing ligand-induced ubiquitination and degradation of activated receptor, which is induced by the E3 ubiquitin ligase c-Cbl. The C-terminal MH2 region but not MH1 region of Smad7 is critical for interaction with c-Cbl to inhibit the ubiquitination of EGFR. Interestingly, wild-type Smad7, but not Smad6 or mutant Smad7, destabilized the EGF-induced complex formation of c-Cbl and EGFR. These data suggest a novel role for Smad7 as a promoter for prolonging the EGFR signal in keratinocyte and skin tissue by reducing its ligand-induced ubiquitination and degradation.
authors.affiliation: Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
authors.forename: Huyen Trang
authors.initials: HT
authors.lastname: Ha Thi
authors.affiliation: Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
authors.forename: Hye-Youn
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
authors.forename: Seo-Won
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Cha Cancer Institute, Cha University, Seongnam, South Korea.
authors.forename: Jin-Muk
authors.initials: JM
authors.lastname: Kang
authors.affiliation: Cha Cancer Institute, Cha University, Seongnam, South Korea Department of Biomedical Science, Cha University, Seongnam, South Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea sthong@gachon.ac.kr.
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017434:Protein Structure, Tertiary; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D051906:Smad7 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D034741:RNA, Small Interfering; D051906:Smad7 Protein; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors