Nerve Growth Factor Signaling from Membrane Microdomains to the Nucleus: Differential Regulation by Caveolins.
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-2potentiateswhile caveolin-1inhibitsnerve 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 p75NTRthat 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.
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. ambre.spencer@gmail.com.|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. ambre.spencer@gmail.com.|East China Normal University, School of Life Sciences, Laboratory of Molecular and Cellular Neurophysiology, Shanghai 200062, China. ambre.spencer@gmail.com.
Ambre
A
Spencer
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. liliyunet@gmail.com.|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. liliyunet@gmail.com.|East China Normal University, School of Life Sciences, Laboratory of Molecular and Cellular Neurophysiology, Shanghai 200062, China. liliyunet@gmail.com.
Lingli
L
Yu
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. vincent.guili@ac-lyon.fr.
Vincent
V
Guili
Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, CGphiMC UMR5534, 69622 Villeurbanne Cedex, France. florie.reynaud@univ-lyon1.fr.
Florie
F
Reynaud
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. emeline.d@gmail.com.|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. emeline.d@gmail.com.|East China Normal University, School of Life Sciences, Laboratory of Molecular and Cellular Neurophysiology, Shanghai 200062, China. emeline.d@gmail.com.
Yindi
Y
Ding
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. jma@bio.ecnu.edu.cn.|East China Normal University, School of Life Sciences, Laboratory of Molecular and Cellular Neurophysiology, Shanghai 200062, China. jma@bio.ecnu.edu.cn.
Ji
J
Ma
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. jj256@gurdon.cam.ac.uk.
Jérôme
J
Jullien
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. david.koubi@finovatis.com.
David
D
Koubi
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. Emmanuel.GAUTHIER@ch-le-vinatier.fr.
Emmanuel
E
Gauthier
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. david.cluet@ens-lyon.fr.|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. david.cluet@ens-lyon.fr.
David
D
Cluet
Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, CGphiMC UMR5534, 69622 Villeurbanne Cedex, France. julien.falk@univ-lyon1.fr.
Julien
J
Falk
Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, CGphiMC UMR5534, 69622 Villeurbanne Cedex, France. valerie.castellani@univ-lyon1.fr.
Valérie
V
Castellani
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. cgyuan@bio.ecnu.edu.cn.|East China Normal University, School of Life Sciences, Laboratory of Molecular and Cellular Neurophysiology, Shanghai 200062, China. cgyuan@bio.ecnu.edu.cn.
Chonggang
C
Yuan
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. brian.rudkin@inserm.fr.|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. brian.rudkin@inserm.fr.|Univ. Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France. brian.rudkin@inserm.fr.
Brian B
BB
Rudkin
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D050882:CREB-Binding Protein / Q000378:metabolism; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051243:Caveolin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020917:Receptor, trkA / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D051242:Caveolin 1; D051243:Caveolin 2; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D020800:Receptor, Nerve Growth Factor; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C068313:Ngfr protein, rat; D020932:Nerve Growth Factor; D050882:CREB-Binding Protein; D020917:Receptor, trkA; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
CREB; NGF; PC12; Trk; caveolin; dorsal root ganglion neurons; growth factor signaling; lipid rafts; membrane microdomains; p75NTR; trafficking