Nerve growth factor in combination with second messenger analogues causes neuronal differentiation of PC12 cells expressing a dominant inhibitory Ras protein without inducing activation of extracellular signal-regulated kinases

2001 ◽  
Vol 14 (9) ◽  
pp. 1445-1454 ◽  
Author(s):  
Gábor Boglári ◽  
József Szeberényi
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Second Messenger ◽  
Nerve Growth ◽  
Ras Protein ◽  
Extracellular Signal

scholarly journals Suppression of Nerve Growth Factor-induced Neuronal Differentiation of PC12 Cells

1996 ◽  
Vol 271 (51) ◽  
pp. 33018-33025 ◽  
Author(s):  
Hideaki Kamata ◽  
Chihiro Tanaka ◽  
Hitoshi Yagisawa ◽  
Satoshi Matsuda ◽  
Yukiko Gotoh ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Nerve Growth

scholarly journals Role of Phosphoinositide 3-Kinase and Endocytosis in Nerve Growth Factor-Induced Extracellular Signal-Regulated Kinase Activation via Ras and Rap1

2000 ◽  
Vol 20 (21) ◽  
pp. 8069-8083 ◽  
Author(s):  
Randall D. York ◽  
Derek C. Molliver ◽  
Savraj S. Grewal ◽  
Paula E. Stenberg ◽  
Edwin W. McCleskey ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Map Kinase ◽  
Pc12 Cells ◽  
Erk Signaling ◽  
Nerve Growth ◽  
Erk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Phosphoinositide 3 Kinase

ABSTRACT Neurotrophins promote multiple actions on neuronal cells including cell survival and differentiation. The best-studied neurotrophin, nerve growth factor (NGF), is a major survival factor in sympathetic and sensory neurons and promotes differentiation in a well-studied model system, PC12 cells. To mediate these actions, NGF binds to the TrkA receptor to trigger intracellular signaling cascades. Two kinases whose activities mediate these processes include the mitogen-activated protein (MAP) kinase (or extracellular signal-regulated kinase [ERK]) and phosphoinositide 3-kinase (PI3-K). To examine potential interactions between the ERK and PI3-K pathways, we studied the requirement of PI3-K for NGF activation of the ERK signaling cascade in dorsal root ganglion cells and PC12 cells. We show that PI3-K is required for TrkA internalization and participates in NGF signaling to ERKs via distinct actions on the small G proteins Ras and Rap1. In PC12 cells, NGF activates Ras and Rap1 to elicit the rapid and sustained activation of ERKs respectively. We show here that Rap1 activation requires both TrkA internalization and PI3-K, whereas Ras activation requires neither TrkA internalization nor PI3-K. Both inhibitors of PI3-K and inhibitors of endocytosis prevent GTP loading of Rap1 and block sustained ERK activation by NGF. PI3-K and endocytosis may also regulate ERK signaling at a second site downstream of Ras, since both rapid ERK activation and the Ras-dependent activation of the MAP kinase kinase kinase B-Raf are blocked by inhibition of either PI3-K or endocytosis. The results of this study suggest that PI3-K may be required for the signals initiated by TrkA internalization and demonstrate that specific endocytic events may distinguish ERK signaling via Rap1 and Ras.

Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells

2006 ◽  
Vol 11 (9) ◽  
pp. 1097-1113 ◽  
Author(s):  
Peng Sun ◽  
Haruko Watanabe ◽  
Kazunori Takano ◽  
Takashi Yokoyama ◽  
Jun-ichi Fujisawa ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Nerve Growth ◽  
Sustained Activation

scholarly journals Adapter Protein SH2-Bβ Undergoes Nucleocytoplasmic Shuttling: Implications for Nerve Growth Factor Induction of Neuronal Differentiation

2004 ◽  
Vol 24 (9) ◽  
pp. 3633-3647 ◽  
Author(s):  
Linyi Chen ◽  
Christin Carter-Su
Keyword(s):  
Plasma Membrane ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Neurite Outgrowth ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Nuclear Export ◽  
Adapter Protein ◽  
Wild Type ◽  
Nerve Growth

ABSTRACT The adapter protein SH2-B has been shown to bind to activated nerve growth factor (NGF) receptor TrkA and has been implicated in NGF-induced neuronal differentiation and the survival of sympathetic neurons. However, the mechanism by which SH2-B enhances and maintains neurite outgrowth is unclear. We examined the ability of truncation mutants to regulate neuronal differentiation and observed that certain truncation mutants localized in the nucleus rather than in the cytoplasm or at the plasma membrane as reported for wild-type SH2-Bβ. Addition of the nuclear export inhibitor leptomycin B caused both overexpressed wild-type and endogenous SH2-Bβ to accumulate in the nucleus of both PC12 cells and COS-7 cells as did deletion of a putative nuclear export sequence (amino acids 224 to 233) or mutation of two critical lysines in that sequence. Deleting or mutating the nuclear export signal caused SH2-Bβ to lose its ability to enhance NGF-induced differentiation of PC12 cells. Neither the NGF-induced phosphorylation of ERKs 1 and 2 nor their subcellular distribution was altered in PC12 cells stably expressing the nuclear export-defective SH2-Bβ(L231A, L233A). These data provide strong evidence that SH2-Bβ shuttles constitutively between the nucleus and cytoplasm. However, SH2-Bβ needs continuous access to the cytoplasm and/or plasma membrane to participate in NGF-induced neurite outgrowth. These data also suggest that the stimulatory effect of SH2-Bβ on NGF-induced neurite outgrowth of PC12 cells is either downstream of ERKs or via some other pathway yet to be identified.

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