Page 34 - ebook

[B. Cell Biology/Stem Cell] B-17

NOTCH1-IC suppresses PAK1 signaling pathway through

direct interaction

So-I Noh¹, Mi-Yeon Kim¹, Eun-Hye Jo¹, Hyung-Ju Lee¹, Hee-Sae Park¹*

¹School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea

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 ofNOTCH1-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.