title: NOTCH1 intracellular domain negatively regulates PAK1 signaling pathway through direct interaction.
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.
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Jo
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Medical Research Center, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Eung-Gook
authors.initials: EG
authors.lastname: Kim
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Keesook
authors.initials: K
authors.lastname: Lee
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. Electronic address: proteome@jnu.ac.kr.
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002465:Cell Movement; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D000099200:Scaffold Protein ILK
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051881:Receptor, Notch1; D054462:p21-Activated Kinases; D000099200:Scaffold Protein ILK; C000605506:GSK3B protein, human
keywords: ILK1; Localization; Migration; NOTCH1-IC; PAK1; Protein–protein interaction