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Molecular and Cellular Biology, August 2007, p. 5565-5574, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.02372-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Integrin-Linked Kinase Controls Notch1 Signaling by Down-Regulation of Protein Stability through Fbw7 Ubiquitin Ligase

Jung-Soon Mo,^1, Mi-Yeon Kim,^1, Seung-Ok Han,¹ In-Sook Kim,¹ Eun-Jung Ann,¹ Kyu Shik Lee,¹ Mi-Sun Seo,¹ Jin-Young Kim,¹ Seung-Chul Lee,² Jeen-Woo Park,³ Eui-Ju Choi,⁴ Jae Young Seong,⁵ Cheol O. Joe,⁶ Reinhard Faessler,⁷ and Hee-Sae Park^1*

Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757,¹ Department of Dermatology, Chonnam National University, Gwangju 501-757,² Department of Biochemistry, College of Natural Sciences, Kyungpook National University, Taegu 702-701,³ National Creative Research Initiative Center for Cell Death, School of Life Science and Biotechnology, Korea University, Seoul 136-701,⁴ Lab of G Protein Coupled Receptors, Graduate School of Medicine, Korea University College of Medicine, Seoul 136-705,⁵ Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Republic of Korea,⁶ Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried D-82152, Germany⁷

Received 20 December 2006/ Returned for modification 1 February 2007/ Accepted 26 April 2007

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.

Published ahead of print on 25 May 2007.

J.-S.M. and M.-Y.K. contributed equally to this work.