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.

Myricetin suppresses p21-activated kinase 1 in human breast cancer MCF-7 cells through downstream signaling of the β-catenin pathway

“…p21-activated kinase 1 (PAK1) was first found as a member of the Pak family (4). Initially, it was cloned from cerebral tissues as p21 kinase (4).…”

“…p21-activated kinase 1 (PAK1) was first found as a member of the Pak family (4). Initially, it was cloned from cerebral tissues as p21 kinase (4). Members of the Pak family play an essential role in immune escape, motility, angiogenesis and genetic regulation (5).…”

A Novel PAK1–Notch1 Axis Regulates Crypt Homeostasis in Intestinal Inflammation

“…The direct association of PAK1 and Notch1 already has been shown, interestingly indicating regulation of PAK1 activity via NICD. 65 Furthermore, Vadlamudi et al 66 showed that phosphorylation of SMRT/ HDAC1 Associated Repressor Protein (SHARP) via PAK1 resulted in repression of Notch target genes. In addition, implications for PAKs inducing a stem cell phenotype already have been made in renal cell carcinoma and in vitro using CRC and pancreatic cancer cell lines.…”

“…Intestinal inflammation results in PAK1 overexpression, thereby tightly controlling the release of Notch1 and bcatenin upon activation and maintaining proper stem cell proliferation and differentiation. 15,65 Loss of PAK1 in this setting leads to diminished differentiation and a more stem cell-like intestinal phenotype as shown by Notch1, OLFM4, LGR5, and Wnt/b-catenin activation, and overexpression with an increase in tumorigenesis (Figure 6).…”

Group I PAKs in myelin formation and repair of the central nervous system: what, when, and how

“…ILK, which plays an essential role in tumorigenesis, has been shown to regulate OPC proliferation and differentiation (Hussain & Macklin, 2017). In addition to ILK, NICD is also reported to interact directly with PAK1 and facilitate PAK1 (and/or ILK) nuclear translocation (Yoon et al ., 2016). HDAC, histone deacetylase; NCoR, nuclear receptor co‐repressor 2; RBP‐J, recombination signal binding protein for immunoglobulin kappa J region.…”