PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity

Qiu, Mengsheng; Green, Steven H.

doi:10.1016/0896-6273(92)90033-a

Cited by 450 publications

(169 citation statements)

References 78 publications

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“…It is known that the kinetics of RTK downregulation directly affects the length of time that downstream signaling pathways are activated and, therefore, the cellular response to the growth factor. In PC12 cells, for example, the length of time that the ERK pathway is activated dictates whether these cells proliferate or differentiate into neurons (Qiu and Green, 1992;York et al, 2000). Thus, different cell types may respond to the same neurotrophic factor in different ways depending on their level of Cbl-3/CD2AP activity, which may explain the remarkably pleiotropic effects of GDNF in vivo (Enomoto, 2005).…”

Section: Discussionmentioning

confidence: 99%

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

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The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance. GFLs promote survival and growth via activation of the receptor tyrosine kinase (RTK) Ret. In sympathetic neurons, the duration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with Ret under basal, unstimulated conditions in neurons. After Ret activation by GDNF, CD2AP dissociates. Similarly, the E3-ligase Cbl-3 interacts with unphosphorylated Ret and dissociates from Ret after Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3 acts as a switch that is triggered by CD2AP and oscillates between inhibition and promotion of Ret degradation. Consistent with the hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing. CD2AP and Cbl-3, therefore, constitute a checkpoint that controls the extent of Ret downregulation and, thereby, the sensitivity of neurons to GFLs.

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Section: Discussionmentioning

confidence: 99%

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

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“…For example, NGF causes a sustained activation of the Trk receptor (21,22) and the MAPK pathway (23)(24)(25)(26). To determine whether NTN or GDNF also promotes long term activation, neurons were treated with NTN or GDNF for up to 30 h before assaying for Ret phosphorylation and MAPK activation.…”

Section: Resultsmentioning

confidence: 99%

Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons

Creedon

Tansey

Baloh

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

202

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Neurturin (NTN) is a neurotrophic factor that shares homology with glial cell line-derived neurotrophic factor (GDNF). Recently, a receptor complex has been identified for GDNF that includes the Ret tyrosine kinase receptor and a glycosylphosphatidylinositol-linked protein termed ''GDNFR␣.'' However, differences in the phenotype of Ret and GDNF knockout animals suggest that Ret has at least one additional ligand. In this report, we demonstrate that NTN induces Ret phosphorylation in primary cultures of rat superior cervical ganglion (SCG) neurons. NTN also caused Ret phosphorylation in fibroblasts that were transfected stably with Ret and GDNFR␣ but not in cells expressing Ret alone. A glycosylphosphatidylinositol-linked protein also was important for NTN and GDNF signaling in SCG neurons; phosphatidylinositol-specific phospholipase C treatment of SCG cultures reduced the ability of NTN to phosphorylate Ret and the ability of NTN or GDNF to activate the mitogen-activated protein kinase pathway. NTN and GDNF also caused sustained activation of Ret and the mitogen-activated protein kinase pathway in SCG neurons. Finally, both NTN and GDNF activated the phosphatidylinositol 3-kinase pathway in SCG neurons, which may be important for the ability of NTN and GDNF to promote neuronal survival. These data indicate that NTN is a physiologically relevant ligand for the Ret receptor and suggest that NTN may have a critical role in the development of many neuronal populations.

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“…For instance, in rat PC12 cells, both EGF and NGF trigger the activation of ERK, but only NGF is able to induce PC12 cell differentiation. The important difference between these two growth factors is that NGF induces sustained ERK phosphorylation and nuclear translocation, whereas EGF only induces transient ERK phosphorylation and no significant nuclear translocation (Qiu and Green, 1992;Traverse et al, 1992;Nguyen et al, 1993). However, the mechanisms by which persistent ERK phosphorylation induces cell growth inhibition or differentiation have not been completely elucidated.…”

Section: Prolonged Erk Phosphorylation Induced By Cpd 5 Is Related Tomentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity

Cited by 450 publications

References 78 publications

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons

K vitamins, PTP antagonism, and cell growth arrest

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