Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction

Fu, Amy Kit Yu; Fu, Wai Yuen; Cheung, Janet; Tsim, Karl Wah Keung; Ip, Fanny Chun Fun; Wang, Jerry Hc; Ip, Nancy Y.

doi:10.1038/86019

Cited by 157 publications

(157 citation statements)

References 43 publications

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“…Cdk5 and p35 have recently also been shown to regulate presynaptic and postsynaptic activity by phosphorylating Munc-18, amphiphysin, and the NR2A subunit of the N-methyl-D-aspartate receptor (7)(8)(9)(10)(11). Cdk5 activity also regulates dopamine signaling by phosphorylating DARPP-32 protein (12) and has been shown to up-regulate the expression of acetylcholine receptor at the neuromuscular junction (13). These studies indicate that Cdk5 is a multifunctional protein kinase in the central nervous system.…”

mentioning

confidence: 75%

“…To determine the target substrate for Cdk5, we based our analysis on the observation that the Cdk5-p35 complex is implicated in neuregulininduced acetylcholine receptor expression at the neuromuscular junction (13). This suggested that ErbB receptors might be a substrate for Cdk5 phosphorylation.…”

Section: Reduced Brain Lipid Phosphorylation and Pi3k Activity Inmentioning

confidence: 99%

“…A clue as to other possible sites of Cdk5 activity in regulating neuronal survival is suggested by the observation that Cdk5 activity, mediated by the neuregulin/ErbB pathway, up-regulates acetylcholine receptor expression at the neuromuscular junction in embryonic myotubes and adult muscle (13). The neuregulins (NRGs) are a class of epidermal growth factor-like molecules; a multigene family encodes them.…”

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confidence: 99%

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Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Jaffe

et al. 2003

Journal of Biological Chemistry

143

119

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The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5؊/؊ mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway.Cyclin-dependent kinase 5 (Cdk5) 1 is a serine/threonine kinase, which is predominantly expressed in postmitotic neurons (1). Cdk5 kinase activity requires association with its neuronspecific activators, p35 and p39. Cdk5 kinase activity is essential for neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (2-4). Recently, Cdk5 has been suggested as contributing to the control of neuronal positioning in Reelin signaling during neural development (5) and to mediate neuronal guidance by regulating semaphorin-3A with Fyn kinase (6). Cdk5 and p35 have recently also been shown to regulate presynaptic and postsynaptic activity by phosphorylating Munc-18, amphiphysin, and the NR2A subunit of the N-methyl-D-aspartate receptor (7-11). Cdk5 activity also regulates dopamine signaling by phosphorylating DARPP-32 protein (12) and has been shown to up-regulate the expression of acetylcholine receptor at the neuromuscular junction (13). These studies indicate that Cdk5 is a multifunctional protein kinase in the central nervous system. Cdk5 has been implicated in both cell survival and programmed cell death in neuronal and nonneuronal systems (14,15). Cells induced to apoptosis by exogenous signals such as staurosporin display increased Cdk5 activity (16,17). Recently, Cdk5 in association with p25, a truncated form of p35, has been thought to be deregulated to produce hyperphosphorylated tau protein and to disrupt the neuronal cytoskeleton, and it may be involved in neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral secrosis, Parkinson's disease, and Niemann-Pick disease (18 -23). On the other hand, Cdk5 may also be involved in neuronal survival. Cdk5 knockout mice exhibit a unique phenotype with perinatal mortality, associated with extensively disrupted cerebral cortical layering due to abnormal neuronal migration, absence of cerebella foliation, and degeneration of neurons...

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mentioning

confidence: 75%

Section: Reduced Brain Lipid Phosphorylation and Pi3k Activity Inmentioning

confidence: 99%

mentioning

confidence: 99%

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Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Jaffe

et al. 2003

Journal of Biological Chemistry

143

119

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“…26 The mysterious nuclear and nucleolar activities of ERBB3 76,78,79 must be unraveled. Further study is needed of the involvement of non-NRG, non-ERBB regulators of ERBB3, such as CDK5, [122][123][124] BRK, 125 SRC, 126 and MET. 120 The fascinating and widely expressed ERBB3 effector EBP1 has thus far been examined mainly in mammary and prostate cells; [154][155][156][157][158][159][160][161][162][163][164] may it be important also in other cancers where ERBB3 is clearly a player, such as lung and melanoma?…”

Section: Discussionmentioning

confidence: 99%

“…123 Furthermore Cdk5 and Erbb3 coimmunoprecipitated, and Cdk5 caused ser/thr phosphorylation on immunoprecipitated Erbb3. These results for muscle were confirmed in Cdk5 −/− knockout mice.…”

Section: Erbb3 Interacting Proteins: Activation Signaling and Regulamentioning

confidence: 94%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Extraneuronal roles of cyclin‐dependent kinase 5

2006

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Cyclin-dependent kinase 5 (Cdk5) is recognized as an essential molecule in the brain, where it regulates several neuronal activities, including cytoskeletal remodeling and synaptic transmission. While activity of Cdk5 has primarily been associated with neurons, there are now substantial data indicating that the kinase's activity and function are more general. An increasing body of evidence has established Cdk5 kinase activity, the presence of the Cdk5 activators, p35 and p39, and Cdk5 functions in non-neuronal cells, including myocytes, pancreatic beta-cells, monocytic and neutrophilic leucocytes, glial cells and germ cells. In this review, we present the diverse roles of Cdk5 in several extraneuronal paradigms. The unique properties of each of the different cell types appear to involve distinct means of Cdk5 regulation and function. The potential mechanisms through which Cdk5 regulates extraneuronal cell activities such as exocytosis, gene transcription, wound healing and senescence are discussed.

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Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction

Cited by 157 publications

References 43 publications

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

The ERBB3 receptor in cancer and cancer gene therapy

Extraneuronal roles of cyclin‐dependent kinase 5

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