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

Ambre Spencer,Lingli Yu,Valérie Castellani,Brian Rudkin,David Koubi,Vincent Guili,Jérôme Jullien,Julien Falk,Chonggang Yuan,Florie Reynaud,Emmanuel Gauthier,Yindi Ding,David Cluet,Ji Ma

doi:10.3390/ijms18040693

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.

Highlights

Membrane microdomains, rich in cholesterol, sphingomyelins, and glycolipids, called lipid rafts, are functional modules of the cell membrane that play a key role in regulating cellular responses to environmental stimuli—e.g., the presence or absence of growth factors or infectious agents—through their capacity to attract or deploy select cellular components [1]
Since Rsk2 is phosphorylated in Cav-1 overexpressing PC12, we investigated if the lack of CREB phosphorylation was due to impaired pRsk translocation
Caveolins are key components of nerve growth factor (NGF) receptor microenvironment that play an important role in the outcome of NGF signaling

Summary

Introduction

Rich in cholesterol, sphingomyelins, and glycolipids, called lipid rafts, are functional modules of the cell membrane that play a key role in regulating cellular responses to environmental stimuli—e.g., the presence or absence of growth factors or infectious agents—through their capacity to attract or deploy select cellular components [1]. The caveolin family consists of two ubiquitously expressed genes, caveolin-1 (Cav-1) and -2 (Cav-2), and one expressed in smooth and skeletal muscles, caveolin-3 (Cav-3) [4,5]. While expression of Cav-1 or Cav-3 is sufficient for the formation of caveolae, expression of Cav-2 is not [6,7,8]. Caveolins influence many diverse physiological processes through their localization in lipid rafts, their role in formation of caveolae, and their specific interaction with both lipid and protein components thereof [10]

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