GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility

The trafficking of T-cells through peripheral tissues and into afferent lymphatic vessels is essential for immune surveillance and an adaptive immune response. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase and regulates numerous cell/tissue-specific functions, including cell survi...

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Main Authors: Mobashar Hussain Urf Turabe Fazil, Prasannan, Praseetha, Wong, Brandon Han Siang, Kottaiswamy, Amuthavalli, Nur Syazwani Mohamed Salim, Sze, Siu Kwan, Verma, Navin Kumar
Other Authors: School of Biological Sciences
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Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/160240
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spelling sg-ntu-dr.10356-1602402023-02-28T17:12:20Z GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility Mobashar Hussain Urf Turabe Fazil Prasannan, Praseetha Wong, Brandon Han Siang Kottaiswamy, Amuthavalli Nur Syazwani Mohamed Salim Sze, Siu Kwan Verma, Navin Kumar School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Interdisciplinary Graduate School (IGS) NTU Institute for Health Technologies Science::Biological sciences T-Lymphocytes T-Cell Migration The trafficking of T-cells through peripheral tissues and into afferent lymphatic vessels is essential for immune surveillance and an adaptive immune response. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase and regulates numerous cell/tissue-specific functions, including cell survival, metabolism, and differentiation. Here, we report a crucial involvement of GSK3β in T-cell motility. Inhibition of GSK3β by CHIR-99021 or siRNA-mediated knockdown augmented the migratory behavior of human T-lymphocytes stimulated via an engagement of the T-cell integrin LFA-1 with its ligand ICAM-1. Proteomics and protein network analysis revealed ongoing interactions among GSK3β, the surface receptor Notch1 and the cytoskeletal regulator CRMP2. LFA-1 stimulation in T-cells reduced Notch1-dependent GSK3β activity by inducing phosphorylation at Ser9 and its nuclear translocation accompanied by the cleaved Notch1 intracellular domain and decreased GSK3β-CRMP2 association. LFA-1-induced or pharmacologic inhibition of GSK3β in T-cells diminished CRMP2 phosphorylation at Thr514. Although substantial amounts of CRMP2 were localized to the microtubule-organizing center in resting T-cells, this colocalization of CRMP2 was lost following LFA-1 stimulation. Moreover, the migratory advantage conferred by GSK3β inhibition in T-cells by CHIR-99021 was lost when CRMP2 expression was knocked-down by siRNA-induced gene silencing. We therefore conclude that GSK3β controls T-cell motility through interactions with CRMP2 and Notch1, which has important implications in adaptive immunity, T-cell mediated diseases and LFA-1-targeted therapies. Ministry of Education (MOE) National Research Foundation (NRF) Published version This work was supported by the grants from the Singapore Ministry of Education (MOE) Academic Research Fund (AcRF) Tier 1 (2014-T1-001-141 and 2020-T1-001-062) and the National Research Foundation Singapore under its Open Fund Large Collaborative Grant (OFLCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). 2022-07-18T03:05:20Z 2022-07-18T03:05:20Z 2021 Journal Article Mobashar Hussain Urf Turabe Fazil, Prasannan, P., Wong, B. H. S., Kottaiswamy, A., Nur Syazwani Mohamed Salim, Sze, S. K. & Verma, N. K. (2021). GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility. Frontiers in Immunology, 12, 680071-. https://dx.doi.org/10.3389/fimmu.2021.680071 1664-3224 https://hdl.handle.net/10356/160240 10.3389/fimmu.2021.680071 34975828 2-s2.0-85122078820 12 680071 en 2014-T1-001-141 2020-T1-001-062 OFLCG18May-0028 Frontiers in Immunology © 2021 Fazil, Prasannan, Wong, Kottaiswamy, Salim, Sze and Verma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
T-Lymphocytes
T-Cell Migration
spellingShingle Science::Biological sciences
T-Lymphocytes
T-Cell Migration
Mobashar Hussain Urf Turabe Fazil
Prasannan, Praseetha
Wong, Brandon Han Siang
Kottaiswamy, Amuthavalli
Nur Syazwani Mohamed Salim
Sze, Siu Kwan
Verma, Navin Kumar
GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility
description The trafficking of T-cells through peripheral tissues and into afferent lymphatic vessels is essential for immune surveillance and an adaptive immune response. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase and regulates numerous cell/tissue-specific functions, including cell survival, metabolism, and differentiation. Here, we report a crucial involvement of GSK3β in T-cell motility. Inhibition of GSK3β by CHIR-99021 or siRNA-mediated knockdown augmented the migratory behavior of human T-lymphocytes stimulated via an engagement of the T-cell integrin LFA-1 with its ligand ICAM-1. Proteomics and protein network analysis revealed ongoing interactions among GSK3β, the surface receptor Notch1 and the cytoskeletal regulator CRMP2. LFA-1 stimulation in T-cells reduced Notch1-dependent GSK3β activity by inducing phosphorylation at Ser9 and its nuclear translocation accompanied by the cleaved Notch1 intracellular domain and decreased GSK3β-CRMP2 association. LFA-1-induced or pharmacologic inhibition of GSK3β in T-cells diminished CRMP2 phosphorylation at Thr514. Although substantial amounts of CRMP2 were localized to the microtubule-organizing center in resting T-cells, this colocalization of CRMP2 was lost following LFA-1 stimulation. Moreover, the migratory advantage conferred by GSK3β inhibition in T-cells by CHIR-99021 was lost when CRMP2 expression was knocked-down by siRNA-induced gene silencing. We therefore conclude that GSK3β controls T-cell motility through interactions with CRMP2 and Notch1, which has important implications in adaptive immunity, T-cell mediated diseases and LFA-1-targeted therapies.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Mobashar Hussain Urf Turabe Fazil
Prasannan, Praseetha
Wong, Brandon Han Siang
Kottaiswamy, Amuthavalli
Nur Syazwani Mohamed Salim
Sze, Siu Kwan
Verma, Navin Kumar
format Article
author Mobashar Hussain Urf Turabe Fazil
Prasannan, Praseetha
Wong, Brandon Han Siang
Kottaiswamy, Amuthavalli
Nur Syazwani Mohamed Salim
Sze, Siu Kwan
Verma, Navin Kumar
author_sort Mobashar Hussain Urf Turabe Fazil
title GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility
title_short GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility
title_full GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility
title_fullStr GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility
title_full_unstemmed GSK3β interacts with CRMP2 and Notch1 and controls T-cell motility
title_sort gsk3β interacts with crmp2 and notch1 and controls t-cell motility
publishDate 2022
url https://hdl.handle.net/10356/160240
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