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Int. J. Mol. Sci. 2017, 18(4), 693; doi:10.3390/ijms18040693

Nerve Growth Factor Signaling from Membrane Microdomains to the Nucleus: Differential Regulation by Caveolins

1
East China Normal University, Key Laboratory of Brain Functional Genomics of the Ministry of Education of PR China, Joint Laboratory of Neuropathogenesis, ECNU, ENS Lyon, CNRS, Shanghai 200062, China
2
Univ. Lyon, Ecole normale supérieure de Lyon, Université Claude Bernard Lyon 1, CNRS, Differentiation & Cell Cycle Group, Laboratoire de Biologie Moléculaire de la Cellule, UMR5239, 69007 Lyon, France
3
East China Normal University, School of Life Sciences, Laboratory of Molecular and Cellular Neurophysiology, Shanghai 200062, China
4
Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, CGphiMC UMR5534, 69622 Villeurbanne Cedex, France
5
Univ. Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editors: Margaret Fahnestock and Keri Martinowich
Received: 29 December 2016 / Revised: 8 March 2017 / Accepted: 13 March 2017 / Published: 24 March 2017
(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)
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Abstract

Membrane microdomains or “lipid rafts” have emerged as essential functional modules of the cell, critical for the regulation of growth factor receptor-mediated responses. Herein we describe the dichotomy between caveolin-1 and caveolin-2, structural and regulatory components of microdomains, in modulating proliferation and differentiation. Caveolin-2 potentiates while caveolin-1 inhibits nerve growth factor (NGF) signaling and subsequent cell differentiation. Caveolin-2 does not appear to impair NGF receptor trafficking but elicits prolonged and stronger activation of MAPK (mitogen-activated protein kinase), Rsk2 (ribosomal protein S6 kinase 2), and CREB (cAMP response element binding protein). In contrast, caveolin-1 does not alter initiation of the NGF signaling pathway activation; rather, it acts, at least in part, by sequestering the cognate receptors, TrkA and p75NTR, at the plasma membrane, together with the phosphorylated form of the downstream effector Rsk2, which ultimately prevents CREB phosphorylation. The non-phosphorylatable caveolin-1 serine 80 mutant (S80V), no longer inhibits TrkA trafficking or subsequent CREB phosphorylation. MC192, a monoclonal antibody towards p75NTR that does not block NGF binding, prevents exit of both NGF receptors (TrkA and p75NTR) from lipid rafts. The results presented herein underline the role of caveolin and receptor signaling complex interplay in the context of neuronal development and tumorigenesis. View Full-Text
Keywords: growth factor signaling; NGF; Trk; p75NTR; trafficking; lipid rafts; membrane microdomains; caveolin; PC12; CREB; dorsal root ganglion neurons growth factor signaling; NGF; Trk; p75NTR; trafficking; lipid rafts; membrane microdomains; caveolin; PC12; CREB; dorsal root ganglion neurons
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Spencer, A.; Yu, L.; Guili, V.; Reynaud, F.; Ding, Y.; Ma, J.; Jullien, J.; Koubi, D.; Gauthier, E.; Cluet, D.; Falk, J.; Castellani, V.; Yuan, C.; Rudkin, B.B. Nerve Growth Factor Signaling from Membrane Microdomains to the Nucleus: Differential Regulation by Caveolins. Int. J. Mol. Sci. 2017, 18, 693.

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