1. NOTCH1 intracellular domain negatively regulates PAK1 signaling pathway through direct interaction
- Author
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Eung-Gook Kim, Eun-Jung Ann, Hye-Jin Lee, Eun-Hye Jo, Mi-Yeon Kim, Ji-Hye Yoon, Ji-Seon Ahn, Hee-Sae Park, Keesook Lee, Se-Hoon Hong, and Jung-Soon Mo
- Subjects
0301 basic medicine ,Immunoblotting ,Protein Serine-Threonine Kinases ,Models, Biological ,MAP2K7 ,Glycogen Synthase Kinase 3 ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,hemic and lymphatic diseases ,Ca2+/calmodulin-dependent protein kinase ,Humans ,c-Raf ,Phosphorylation ,Receptor, Notch1 ,Protein kinase A ,Molecular Biology ,Protein kinase B ,Hippo signaling pathway ,Binding Sites ,Glycogen Synthase Kinase 3 beta ,Microscopy, Confocal ,Chemistry ,Akt/PKB signaling pathway ,Cell Biology ,Cell biology ,HEK293 Cells ,030104 developmental biology ,p21-Activated Kinases ,Hes3 signaling axis ,030220 oncology & carcinogenesis ,embryonic structures ,cardiovascular system ,RNA Interference ,sense organs ,biological phenomena, cell phenomena, and immunity ,HeLa Cells ,Protein Binding ,Signal Transduction - Abstract
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.
- Published
- 2016