scholarly journals Noncanonical Function of MEKK2 and MEK5 PB1 Domains for Coordinated Extracellular Signal-Regulated Kinase 5 and c-Jun N-Terminal Kinase Signaling

2007 ◽  
Vol 27 (12) ◽  
pp. 4566-4577 ◽  
Author(s):  
Kazuhiro Nakamura ◽  
Gary L. Johnson
Keyword(s):  
Ternary Complex ◽  
Mitogen Activated Protein Kinase ◽  
Docking Site ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Differential Binding ◽  
Pb1 Domain ◽  
Jnk Activation

ABSTRACT MEKK2 and MEK5 encode Phox/Bem1p (PB1) domains that heterodimerize with one another. MEKK2, MEK5, and extracellular signal-related kinase 5 (ERK5) form a ternary complex through interactions involving the MEKK2 and MEK5 PB1 domains and a 34-amino-acid C-terminal extension of the MEK5 PB1 domain. This C-terminal extension encodes an ERK5 docking site required for MEK5 activation of ERK5. The PB1 domains bind in a front-to-back arrangement, with a cluster of basic amino acids in the front of the MEKK2 PB1 domain binding to the back-end acidic clusters of the MEK5 PB1 domain. The C-terminal moiety, including the acidic cluster of the MEKK2 PB1 domain, is not required for MEK5 binding and binds MKK7. Quiescent MEKK2 preferentially binds MEK5, and MEKK2 activation results in ERK5 activation. Activated MEKK2 binds and activates MKK7, leading to JNK activation. The findings define how the MEKK2 and MEK5 PB1 domains are uniquely used for differential binding of two mitogen-activated protein kinase kinases, MEK5 and MKK7, for the coordinated control of ERK5 and c-Jun N-terminal kinase activation.

scholarly journals Novel Molecular Basis for Synapse Formation: Small Non-coding Vault RNA Functions as a Riboregulator of MEK1 to Modulate Synaptogenesis

2021 ◽  
Vol 14 ◽  
Author(s):  
Shuji Wakatsuki ◽  
Toshiyuki Araki
Keyword(s):  
Protein Kinase ◽  
Molecular Basis ◽  
Synapse Formation ◽  
Regulatory Mechanism ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Small non-coding vault RNAs (vtRNAs) have been described as a component of the vault complex, a hollow-and-barrel-shaped ribonucleoprotein complex found in most eukaryotes. It has been suggested that the function of vtRNAs might not be limited to simply maintaining the structure of the vault complex. Despite the increasing research on vtRNAs, little is known about their physiological functions. Recently, we have shown that murine vtRNA (mvtRNA) up-regulates synaptogenesis by activating the mitogen activated protein kinase (MAPK) signaling pathway. mvtRNA binds to and activates mitogen activated protein kinase 1 (MEK1), and thereby enhances MEK1-mediated extracellular signal-regulated kinase activation. Here, we introduce the regulatory mechanism of MAPK signaling in synaptogenesis by vtRNAs and discuss the possibility as a novel molecular basis for synapse formation.

scholarly journals Opposing Roles of the Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Cascades in Ras-Mediated Downregulation of Tropomyosin

2002 ◽  
Vol 22 (7) ◽  
pp. 2304-2317 ◽  
Author(s):  
Janiel M. Shields ◽  
Heena Mehta ◽  
Kevin Pruitt ◽  
Channing J. Der
Keyword(s):  
Cell Lines ◽  
Human Tumor ◽  
Mitogen Activated Protein Kinase ◽  
Representational Difference Analysis ◽  
Morphological Transformation ◽  
Human Tumor Cell Lines ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT We showed previously that activated Ras, but not Raf, causes transformation of RIE-1 epithelial cells, demonstrating the importance of Raf-independent pathways in mediating Ras transformation. To assess the mechanism by which Raf-independent effector signaling pathways contribute to Ras-mediated transformation, we recently utilized representational difference analysis to identify genes expressed in a deregulated fashion by activated Ras but not Raf. One gene identified in these analyses encodes for α-tropomyosin. Therefore, we evaluated the mechanism by which Ras causes the downregulation of tropomyosin expression. By using RIE-1 cells that harbor inducible expression of activated H-Ras(12V), we determined that the downregulation of tropomyosin expression correlated with the onset of morphological transformation. We found that the reversal of Ras transformation caused by inhibition of extracellular signal-regulated kinase activation corresponded to a restoration of tropomyosin expression. Inhibition of p38 activity in Raf-expressing RIE-1 cells caused both morphological transformation and loss of tropomyosin expression. Thus, a reduction in tropomyosin expression correlated strictly with morphological transformation of RIE-1 cells. However, forced overexpression of tropomyosin in Ras-transformed cells did not reverse morphological or growth transformation, a finding consistent with the possibility that multiple changes in gene expression contribute to Ras transformation. We also determined that tropomyosin expression was low in two human tumor cell lines, DLD-1 and HT1080, that harbor endogenous mutated alleles of ras, but high in transformation-impaired, derivative cell lines in which the mutant ras allele has been genetically deleted. Finally, treatment with azadeoxycytidine restored tropomyosin expression in Ras-transformed RIE-1, HT1080, and DLD-1 cells, suggesting a role for DNA methylation in downregulating tropomyosin expression.

scholarly journals A Novel Mitogen-Activated Protein Kinase Docking Site in the N Terminus of MEK5α Organizes the Components of the Extracellular Signal-Regulated Kinase 5 Signaling Pathway

2005 ◽  
Vol 25 (22) ◽  
pp. 9820-9828 ◽  
Author(s):  
Jan Seyfried ◽  
Xin Wang ◽  
Giorgi Kharebava ◽  
Cathy Tournier
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Docking Site ◽  
Cellular Survival ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
N Terminus ◽  
Mitogen Activated Protein ◽  
Mapk Kinases

ABSTRACT The alternative splicing of the mek5 gene gives rise to two isoforms. MEK5β lacks an extended N terminus present in MEK5α. Comparison of their activities led us to identify a novel mitogen-activated protein kinase (MAPK) docking site in the N terminus of MEK5α that is distinct from the consensus motif identified in the other MAPK kinases. It consists of a cluster of acidic residues at position 61 and positions 63 to 66. The formation of the MEK5/extracellular signal-regulated kinase 5 (ERK5) complex is critical for MEK5 to activate ERK5, to increase transcription via MEF2, and to enhance cellular survival in response to osmotic stress. Certain mutations in the ERK5 docking site that prevent MEK5/ERK5 interaction also abrogate the ability of MEKK2 to bind and activate MEK5. However, the identification of MEK5α mutants with selective binding defect demonstrates that the MEK5/ERK5 interaction does not rely on the binding of MEK5α to MEKK2 via their respective PB1 domains. Altogether these results establish that the N terminus of MEK5α is critical for the specific organization of the components of the ERK5 signaling pathway.

scholarly journals Regulation of Sprouty Stability by Mnk1-Dependent Phosphorylation

2006 ◽  
Vol 26 (5) ◽  
pp. 1898-1907 ◽  
Author(s):  
John DaSilva ◽  
Lizhong Xu ◽  
Hong Joo Kim ◽  
W. Todd Miller ◽  
Dafna Bar-Sagi
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Receptor Tyrosine Kinase ◽  
Antagonistic Effect ◽  
Serine Phosphorylation ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Sprouty (Spry) proteins are negative feedback modulators of receptor tyrosine kinase pathways in Drosophila melanogaster and mammals. Mammalian Spry proteins have been shown to undergo tyrosine and serine phosphorylation in response to growth factor stimulation. While several studies have addressed the function of tyrosine phosphorylation of Spry, little is known about the significance of Spry serine phosphorylation. Here we identify mitogen-activated protein kinase-interacting kinase 1 (Mnk1) as the kinase that phosphorylates human Spry2 (hSpry2) on serines 112 and 121. Mutation of these serine residues to alanine or inhibition of Mnk1 activity increases the rate of ligand-induced degradation of hSpry2. Conversely, enhancement of serine phosphorylation achieved through either the inhibition of cellular phosphatases or the expression of active Mnk1 results in the stabilization of hSpry2. Previous studies have shown that growth factor stimulation induces the proteolytic degradation of hSpry2 by stimulating tyrosine phosphorylation on hSpry2, which in turn promotes c-Cbl binding and polyubiquitination. A mutant of hSpry2 that is deficient in serine phosphorylation displays enhanced tyrosine phosphorylation and c-Cbl binding, indicating that serine phosphorylation stabilizes hSpry2 by exerting an antagonistic effect on tyrosine phosphorylation. Moreover, loss of serine phosphorylation and the resulting enhanced degradation of hSpry2 impair its capacity to antagonize fibroblast growth factor-induced extracellular signal-regulated kinase activation. Our results imply that Mnk1-mediated serine phosphorylation of hSpry2 constitutes a regulatory mechanism to extend the temporal range of Spry activity.

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