NOTCH1 intracellular domain negatively regulates PAK1 signaling pathway through direct interaction

作者：Yoon Ji Hye; Mo Jung Soon; Ann Eun Jung; Ahn Ji Seon; Jo Eun Hye; Lee Hye Jin; Hong Se Hoon; Kim Mi Yeon; Kim Eung Gook; Lee Keesook; Park Hee Sae^*

来源：Biochimica et Biophysica Acta-Molecular Cell Research, 2016, 1863(2): 179-188.

DOI：10.1016/j.bbamcr.2015.11.001

• NOTCH1-IC
• PAK1
• ILK1
• Localization
• Protein-protein interaction
• Migration

p21-Activated kinase 1 (PAK1) is a serine/threonine protein kinase implicated in cytoskeletal remodeling and cell motility. Recent studies have shown that it also promotes cell proliferation, regulates apoptosis, and increases cell transformation and invasion. In this study, we showed that NOTCH1 intracellular domain (NOTCH1-IC) negatively regulated PAK1 signaling pathway. We found a novel interaction between NOTCH1-IC and PAK1. Overexpression of NOTCH1-IC decreased PAK1-induced integrin-linked kinase 1 (ILK1) phosphorylation, whereas inhibition of NOTCH1 signaling increased PAK1-induced ILK1 phosphorylation. Notably, ILK1 phosphorylation was higher in PS1,2(-/-) cells than in PS1,2(+/+) cells. As expected, overexpression of NOTCH1-IC decreased ILK1-induced phosphorylation of glycogen synthase kinase 3 beta (GSK-3beta). Furthermore, NOTCH1-IC disrupted the interaction of PAK1 with ILK1 and altered PAK1 localization by directly interacting with it This inhibitory effect of NOTCH1-IC on the PAK1 signaling pathway was mediated by the binding of NOTCH1-IC to PAK1 and by the alteration of PAK1 localization. Together, these results suggest that NOTCH1-IC is a new regulator of the PAK1 signaling pathway that directly interacts with PAK1 and regulates its shuttling between the nucleus and the cytoplasm.

• 出版日期2016-2