title: Integrin-linked kinase controls Notch1 signaling by down-regulation of protein stability through Fbw7 ubiquitin ligase.
abstract: Integrin-linked kinase (ILK) is a scaffold and protein kinase that acts as a pivotal effector in integrin signaling for various cellular functions. In this study, we found that ILK remarkably reduced the protein stability of Notch1 through Fbw7. The kinase activity of ILK was essential for the inhibition of Notch1 signaling. Notably, the protein level and transcriptional activity of the endogenous Notch1 intracellular domain (Notch1-IC) were higher in ILK-null cells than in ILK wild-type cells, and the level of endogenous Notch1-IC was increased by the blocking of the proteasome, suggesting that ILK enhances the proteasomal degradation of Notch1-IC. ILK directly bound and phosphorylated Notch1-IC, thereby facilitating proteasomal protein degradation through Fbw7. Furthermore, we found down-regulation of Notch1-IC and up-regulation of ILK in basal cell carcinoma and melanoma patients but not in squamous cell carcinoma patients. These results suggest that ILK down-regulated the protein stability of Notch1-IC through the ubiquitin-proteasome pathway by means of Fbw7.
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Yongbong-dong, Buk-ku, Gwangju 500-757, Republic of Korea.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Seung-Ok
authors.initials: SO
authors.lastname: Han
authors.forename: In-Sook
authors.initials: IS
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.forename: Kyu Shik
authors.initials: KS
authors.lastname: Lee
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Seo
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Seung-Chul
authors.initials: SC
authors.lastname: Lee
authors.forename: Jeen-Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.forename: Cheol O
authors.initials: CO
authors.lastname: Joe
authors.forename: Reinhard
authors.initials: R
authors.lastname: Faessler
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000201:enzymology / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics; D002467:Cell Nucleus / Q000201:enzymology; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000201:enzymology; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics; D013816:Thermodynamics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D000099200:Scaffold Protein ILK
chemical_list: D017346:Protein Serine-Threonine Kinases; D051881:Receptor, Notch1; D044843:SKP Cullin F-Box Protein Ligases; D012694:Serine; D000099200:Scaffold Protein ILK; C497762:Notch1 protein, mouse