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Mol. Cell. Biol. doi:10.1128/MCB.02372-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Integrin-Linked Kinase controls Notch1 signaling by down-regulation of protein stability through Fbw7 ubiquitin ligase

Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea; Department of Dermatology, Chonnam National University, Gwangju 501-757, Republic of Korea; Department of Biochemistry, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Republic of Korea; National Creative Research Initiative Center for Cell Death, School of Life Science and Biotechnology, Korea University, Seoul 136-701, Republic of Korea; Lab of G protein coupled receptors, Graduate School of Medicine, Korea University College of Medicine, Seoul 136-705, Republic of Korea; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Republic of Korea; Max Planck Institute of Biochemistry, Department of Molecular Medicine, Martinsried D-82152, Germany

^* To whom correspondence should be addressed. Email: proteome{at}jnu.ac.kr.

	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 endogenous Notch1-IC was higher in the ILK null cells than in ILK wild-type cells, and the endogenous Notch1-IC was increased by the blocking of the proteasome representing the enhancement of the proteasomal degradation of Notch1-IC by ILK. ILK directly bound and phosphorylated Notch1-IC thereby facilitates proteasomal protein degradation through Fbw7. Furthermore, we found that down-regulation of Notch1-IC and up-regulation of ILK in Basal Cell Carcinoma (BCC) and melanoma patients, but not in squamous cell carcinoma (SCC). These results suggest that ILK down-regulated the protein stability of Notch1-IC through the ubiquitin-proteasome pathway by means of Fbw7.