MAP kinase/ERK kinase 1 (MEK1) phosphorylates regulator of calcineurin 1 (RCAN1) to regulate neuronal differentiation

2021 ◽  
Author(s):  
Seon Sook Kim ◽  
Eun Hye Lee ◽  
Jin Hak Shin ◽  
Su Ryeon Seo
Keyword(s):  
Map Kinase ◽  
Neuronal Differentiation ◽  
Erk Kinase

scholarly journals The beta-PDGF receptor induces neuronal differentiation of PC12 cells.

1992 ◽  
Vol 3 (5) ◽  
pp. 545-553 ◽  
Author(s):  
L E Heasley ◽  
G L Johnson
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Common Property ◽  
Map Kinases ◽  
Kinase Activity ◽  
Pdgf Receptor ◽  
Basic Fgf

Expression of the mouse beta-PDGF receptor by gene transfer confers PDGF-dependent and reversible neuronal differentiation of PC12 pheochromocytoma cells similar to that observed in response to NGF and basic FGF. A common property of the PDGF, NGF, and basic FGF-induced differentiation response is the requirement for constant exposure of cells to the growth factor. To test the hypothesis that a persistent level of growth factor receptor signaling is required for the maintenance of the neuronal phenotype, we examined the regulation of the serine/threonine-specific MAP kinases after either short- (10 min) or long-term (24 h) stimulation with growth factors. Mono Q FPLC resolved two peaks of growth factor-stimulated MAP kinase activity that coeluted with tyrosine phosphorylated 41- and 43-kDa polypeptides. MAP kinase activity was markedly stimulated (approximately 30-fold) within 5 min of exposure to several growth factors (PDGF, NGF, basic FGF, EGF, and IGF-I), but was persistently maintained at 10-fold above basal activity after 24 h only by the growth factors that also induce PC12 cell differentiation (PDGF, NGF, and basic FGF). Thus the beta-PDGF receptor is in a subset of tyrosine kinase-encoded growth factor receptors that are capable of maintaining continuous signals required for differentiation of PC12 cells. These signals include the constitutive activation of cytoplasmic serine/threonine protein kinases.

scholarly journals GTPase-deficient G alpha 16 and G alpha q induce PC12 cell differentiation and persistent activation of cJun NH2-terminal kinases.

1996 ◽  
Vol 16 (2) ◽  
pp. 648-656 ◽  
Author(s):  
L E Heasley ◽  
B Storey ◽  
G R Fanger ◽  
L Butterfield ◽  
J Zamarripa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Protein Kinase ◽  
Map Kinase ◽  
Neurite Outgrowth ◽  
Neuronal Differentiation ◽  
Pc12 Cells ◽  
Pc12 Cell ◽  
Jnk Activation ◽  
G Alpha Q ◽  
Constitutively Active

Persistent stimulation of specific protein kinase pathways has been proposed as a key feature of receptor tyrosine kinases and intracellular oncoproteins that signal neuronal differentiation of rat pheochromocytoma (PC12) cells. Among the protein serine/threonine kinases identified to date, the p42/44 mitogen-activated protein (MAP) kinases have been highlighted for their potential role in signalling PC12 cell differentiation. We report here that retrovirus-mediated expression of GTPase-deficient, constitutively active forms of the heterotrimeric Gq family members, G alpha qQ209L and G alpha 16Q212L, in PC12 cells induces neuronal differentiation as indicated by neurite outgrowth and the increased expression of voltage-dependent sodium channels. Differentiation was not observed after cellular expression of GTPase-deficient forms of alpha i2 or alpha 0, indicating selectivity for the Gq family of G proteins. As predicted, overexpression of alpha qQ209L and alpha 16Q212L constitutively elevated basal phospholipase C activity approximately 10-fold in PC12 cells. Significantly, little or no p42/44 MAP kinase activity was detected in PC12 cells differentiated with alpha 16Q212L or alpha qQ209L, although these proteins were strongly activated following expression of constitutively active cRaf-1. Rather, a persistent threefold activation of the cJun NH2-terminal kinases (JNKs) was observed in PC12 cells expressing alpha qQ209L and alpha 16Q212L. This level of JNK activation was similar to that achieved with nerve growth factor, a strong inducer of PC12 cell differentiation. Supportive of a role for JNK activation in PC12 cell differentiation, retrovirus-mediated overexpression of cJun, a JNK target, in PC12 cells induced neurite outgrowth. The results define a p42/44 MAP kinase-independent mechanism for differentiation of PC12 cells and suggest that persistent activation of the JNK members of the proline-directed protein kinase family by GTPase-deficient G alpha q and G alpha 16 subunits is sufficient to induce differentiation of PC12 cells.

scholarly journals C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation

2014 ◽  
Vol 111 (37) ◽  
pp. E3929-E3936 ◽  
Author(s):  
Edmund Nesti ◽  
Glen M. Corson ◽  
Maxwell McCleskey ◽  
Jon A. Oyer ◽  
Gail Mandel
Keyword(s):  
Map Kinase ◽  
Neuronal Differentiation ◽  
Terminal Domain

scholarly journals Interleukin-6-induced STAT3 transactivation and Ser727 phosphorylation involves Vav, Rac-1 and the kinase SEK-1/MKK-4 as signal transduction components

2000 ◽  
Vol 347 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Jan-Jacob SCHURINGA ◽  
Luigi J. C. JONK ◽  
Wim H. A. DOKTER ◽  
Edo VELLENGA ◽  
Wiebe KRUIJER
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Map Kinase ◽  
Hepg2 Cells ◽  
Mek Inhibitor ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Kinase

In the present study, signal transducer and activator of transcription 3 (STAT3) Ser727 phosphorylation and transactivation was investigated in relation to activation of mitogen-activated protein (MAP) kinase family members including extracellular-signal-regulated protein kinase (ERK)-1, c-Jun N-terminal kinase (JNK)-1 and p38 (‘reactivating kinase’) in response to interleukin (IL)-6 stimulation. Although IL-6 can activate ERK-1 in HepG2 cells, STAT3 transactivation and Ser727 phosphorylation were not reduced by using the MAP kinase/ERK kinase (MEK) inhibitor PD98059 or by overexpression of dominant-negative Raf. IL-6 did not activate JNK-1 in HepG2 cells and STAT3 was a poor substrate for JNK-1 activated by anisomycin, excluding a role for JNK1 in IL-6-induced STAT3 activation. However, SEK-1/MKK-4 [where SEK-1 stands for stress-activated protein kinase (SAPK)/ERK kinase 1, and MKK-4 stands for MAP kinase kinase 4] was activated in response to IL-6 and overexpression of dominant-negative SEK-1/MKK-4(A-L) reduced both IL-6-induced STAT3 Ser727 phosphorylation as well as STAT3 transactivation. Subsequently, the SEK-1/MKK-4 upstream components Vav, Rac-1 and MEKK were identified as components of a signal transduction cascade that leads to STAT3 transactivation in response to IL-6 stimulation. Furthermore, inhibition of p38 kinase activity with the inhibitor SB203580 did not block STAT3 Ser727 phosphorylation but rather increased both basal as well as IL-6-induced STAT3 transactivation, indicating that p38 may act as a negative regulator of IL-6-induced STAT3 transactivation through a presently unknown mechanism. In conclusion, these data indicate that IL-6-induced STAT3 transactivation and Ser727 phosphorylation is independent of ERK-1 or JNK-1 activity, but involves a gp130 receptor-signalling cascade that includes Vav, Rac-1, MEKK and SEK-1/MKK-4 as signal transduction components.

scholarly journals Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors

2019 ◽  
Vol 20 (22) ◽  
pp. 5592 ◽  
Author(s):  
Halawa ◽  
Eskandrani ◽  
Elgammal ◽  
Hassan ◽  
Hassan ◽  
...  
Keyword(s):  
Map Kinase ◽  
Rational Design ◽  
Binding Pocket ◽  
Kinase Domain ◽  
Effector Proteins ◽  
Cellular Functions ◽  
Oncogenic Signaling ◽  
Design And Synthesis ◽  
Mitogen Activated Protein ◽  
Erk Kinase

Protein kinases orchestrate diverse cellular functions; however, their dysregulation is linked to metabolic dysfunctions, associated with many diseases, including cancer. Mitogen-Activated Protein (MAP) kinase is a notoriously oncogenic signaling pathway in human malignancies, where the extracellular signal-regulated kinases (ERK1/2) are focal serine/threonine kinases in the MAP kinase module with numerous cytosolic and nuclear mitogenic effector proteins. Subsequently, hampering the ERK kinase activity by small molecule inhibitors is a robust strategy to control the malignancies with aberrant MAP kinase signaling cascades. Consequently, new heterocyclic compounds, containing a sulfonamide moiety, were rationally designed, aided by the molecular docking of the starting reactant 1-(4-((4-methylpiperidin-1-yl)sulfonyl)phenyl)ethan-1-one (3) at the ATP binding pocket of the ERK kinase domain, which was relying on the molecular extension tactic. The identities of the synthesized compounds (4–33) were proven by their spectral data and elemental analysis. The target compounds exhibited pronounced anti-proliferative activities against the MCF-7, HepG-2, and HCT-116 cancerous cell lines with potencies reaching a 2.96 μM for the most active compound (22). Moreover, compounds 5, 9, 10b, 22, and 28 displayed a significant G2/M phase arrest and induction of the apoptosis, which was confirmed by the cell cycle analysis and the flow cytometry. Thus, the molecular extension of a small fragment bounded at the ERK kinase domain is a valid tactic for the rational synthesis of the ERK inhibitors to control various human malignancies.

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