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

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.

Understanding the interplay of membrane trafficking, cell surface mechanics, and stem cell differentiation

“…Considering the above mentioned relationship between plasma membrane tension, eisosomes, and TORC2 in yeast [92] , [93] , it is tempting to speculate that tension, caveolar endocytosis and differentiation could be connected over mTORC2. Indeed, a role of caveolin-1 and - 2 has been described for neuronal stem cell differentiation via Nerve Growth Factor signaling [118] . In breast cancer stem cells, caveolin-1 expression was upregulated in and needed for the self-renewal ability of those cells [119] .…”

Proteomics as a Complementary Technique to Characterize Bladder Cancer

“…Similarly, Cav-3 is also involved in regulating the GPCR signaling pathway mediated by adenylyl cyclase [ 186 ]. In contrast, Cav-2 influences the formation of caveolae by triggering the caveolin-1-mediated pathway and also lessens the inhibiting effects of Cav-1 onto the nerve growth factor (NGF) pathway and subsequent cell differentiation [ 187 , 188 ]. Moreover, whereas the expression of Cav-3 is circumscribed to muscle cells, the expression of Cav-1 and Cav-2 identifies the presence of adipocytes, fibroblasts, and other endothelial cells.…”

Genome-Wide DNA Methylation Analysis in Male Methamphetamine Users With Different Addiction Qualities

“…CAV2, a membrane microdomain or "lipid raft, " has emerged as an essential functional module of the cell that is critical for the regulation of nerve growth factor (NGF) signaling and subsequent cell differentiation (67). BDNF increased the level of CAV2 in the rafts of hippocampal neurons for synapse development (68).…”