Integrin-linked kinase controls Notch1 signaling by down-regulation of protein stability through Fbw7 ubiquitin ligase.
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.
Mo
Jung-Soon
JS
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Yongbong-dong, Buk-ku, Gwangju 500-757, Republic of Korea.
Kim
Mi-Yeon
MY
Han
Seung-Ok
SO
Kim
In-Sook
IS
Ann
Eun-Jung
EJ
Lee
Kyu Shik
KS
Seo
Mi-Sun
MS
Kim
Jin-Young
JY
Lee
Seung-Chul
SC
Park
Jeen-Woo
JW
Choi
Eui-Ju
EJ
Seong
Jae Young
JY
Joe
Cheol O
CO
Faessler
Reinhard
R
Park
Hee-Sae
HS
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
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