MKP-2: out of the DUSP-bin and back into the limelight

2012 ◽  
Vol 40 (1) ◽  
pp. 235-239 ◽  
Author(s):  
Ahmed Lawan ◽  
Emma Torrance ◽  
Sameer Al-Harthi ◽  
Muhannad Shweash ◽  
Sulaiman Alnasser ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Metabolic Disorders ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Extracellular Signal Regulated Kinase ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases

The MKPs (mitogen-activated protein kinase phosphatases) are a family of at least ten DUSPs (dual-specificity phosphatases) which function to terminate the activity of the MAPKs (mitogen-activated protein kinases). Several members have already been demonstrated to have distinct roles in immune function, cancer, fetal development and metabolic disorders. One DUSP of renewed interest is the inducible nuclear phosphatase MKP-2, which dephosphorylates both ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase) in vitro. Recently, the understanding of MKP-2 function has been advanced due to the development of mouse knockout models, which has resulted in the discovery of novel roles for MKP-2 in the regulation of sepsis, infection and cell-cycle progression that are distinct from those of other DUSPs. However, many functions for MKP-2 still await to be characterized.

Intrinsic and acquired resistance to MEK1/2 inhibitors in cancer

2014 ◽  
Vol 42 (4) ◽  
pp. 776-783 ◽  
Author(s):  
Matthew J. Sale ◽  
Simon J. Cook
Keyword(s):  
Protein Kinase ◽  
Present Article ◽  
Acquired Resistance ◽  
Mitogen Activated Protein Kinase ◽  
Inhibitor Activity ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Signalling Cascade

Recent clinical data with BRAF and MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors have demonstrated the remarkable potential of targeting the RAF–MEK1/2–ERK1/2 signalling cascade for the treatment of certain cancers. Despite these advances, however, only a subset of patients respond to these agents in the first instance, and, of those that do, acquired resistance invariably develops after several months. Studies in vitro have identified various mechanisms that can underpin intrinsic and acquired resistance to MEK1/2 inhibitors, and these frequently recapitulate those observed clinically. In the present article, we review these mechanisms and also discuss recent advances in our understanding of how MEK1/2 inhibitor activity is influenced by pathway feedback.

scholarly journals Extracellular Signal-Regulated Kinase 2-Dependent Phosphorylation Induces Cytoplasmic Localization and Degradation of p21Cip1

2009 ◽  
Vol 29 (12) ◽  
pp. 3379-3389 ◽  
Author(s):  
Chae Young Hwang ◽  
Cheolju Lee ◽  
Ki-Sun Kwon
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Nuclear Antigen ◽  
Inhibitory Protein ◽  
Cycle Progression ◽  
Double Mutation ◽  
Extracellular Signal Regulated Kinase ◽  
Epidermal Growth Factor Treatment ◽  
Extracellular Signal

ABSTRACT p21Cip1 is an inhibitor of cell cycle progression that promotes G1-phase arrest by direct binding to cyclin-dependent kinase and proliferating cell nuclear antigen. Here we demonstrate that mitogenic stimuli, such as epidermal growth factor treatment and oncogenic Ras transformation, induce p21Cip1 downregulation at the posttranslational level. This downregulation requires the sustained activation of extracellular signal-regulated kinase 2 (ERK2), which directly interacts with and phosphorylates p21Cip1, promoting p21Cip1 nucleocytoplasmic translocation and ubiquitin-dependent degradation, thereby resulting in cell cycle progression. ERK1 is not likely involved in this process. Phosphopeptide analysis of in vitro ERK2-phosphorylated p21Cip1 revealed two phosphorylation sites, Thr57 and Ser130. Double mutation of these sites abolished ERK2-mediated p21Cip1 translocation and degradation, thereby impairing ERK2-dependent cell cycle progression at the G1/S transition. These results indicate that ERK2 activation transduces mitogenic signals, at least in part, by downregulating the cell cycle inhibitory protein p21Cip1.

Dual-specificity phosphatases: critical regulators with diverse cellular targets

2009 ◽  
Vol 418 (3) ◽  
pp. 475-489 ◽  
Author(s):  
Kate I. Patterson ◽  
Tilman Brummer ◽  
Philippa M. O'brien ◽  
Roger J. Daly
Keyword(s):  
Protein Kinase ◽  
Sequence Similarity ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Targets ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases ◽  
The One ◽  
And Function

DUSPs (dual-specificity phosphatases) are a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. DUSPs have been implicated as major modulators of critical signalling pathways that are dysregulated in various diseases. DUSPs can be divided into six subgroups on the basis of sequence similarity that include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases (Cdc is cell division cycle), PTENs (phosphatase and tensin homologues deleted on chromosome 10), myotubularins, MKPs (mitogen-activated protein kinase phosphatases) and atypical DUSPs. Of these subgroups, a great deal of research has focused on the characterization of the MKPs. As their name suggests, MKPs dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 with specificity distinct from that of individual MKP proteins. Atypical DUSPs are mostly of low-molecular-mass and lack the N-terminal CH2 (Cdc25 homology 2) domain common to MKPs. The discovery of most atypical DUSPs has occurred in the last 6 years, which has initiated a large amount of interest in their role and regulation. In the past, atypical DUSPs have generally been grouped together with the MKPs and characterized for their role in MAPK signalling cascades. Indeed, some have been shown to dephosphorylate MAPKs. The current literature hints at the potential of the atypical DUSPs as important signalling regulators, but is crowded with conflicting reports. The present review provides an overview of the DUSP family before focusing on atypical DUSPs, emerging as a group of proteins with vastly diverse substrate specificity and function.

scholarly journals Human phosphatase CDC14A regulates actin organization through dephosphorylation of epithelial protein lost in neoplasm

2017 ◽  
Vol 114 (20) ◽  
pp. 5201-5206 ◽  
Author(s):  
Nan-Peng Chen ◽  
Borhan Uddin ◽  
Robert Hardt ◽  
Wen Ding ◽  
Marko Panic ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Poor Prognosis ◽  
Cell Cycle Progression ◽  
Mitotic Exit ◽  
Actin Dynamics ◽  
Cycle Progression ◽  
Actin Organization ◽  
Extracellular Signal Regulated Kinase ◽  
Dual Specificity ◽  
Extracellular Signal

CDC14 is an essential dual-specificity phosphatase that counteracts CDK1 activity during anaphase to promote mitotic exit in Saccharomyces cerevisiae. Surprisingly, human CDC14A is not essential for cell cycle progression. Instead, it regulates cell migration and cell adhesion. Little is known about the substrates of hCDC14A and the counteracting kinases. Here, we combine phospho-proteome profiling and proximity-dependent biotin identification to identify hCDC14A substrates. Among these targets were actin regulators, including the tumor suppressor eplin. hCDC14A counteracts EGF-induced rearrangements of actin cytoskeleton by dephosphorylating eplin at two known extracellular signal-regulated kinase sites, serine 362 and 604. hCDC14APD and eplin knockout cell lines exhibited down-regulation of E-cadherin and a reduction in α/β-catenin at cell–cell adhesions. Reduction in the levels of hCDC14A and eplin mRNA is frequently associated with colorectal carcinoma and is correlated with poor prognosis. We therefore propose that eplin dephosphorylation by hCDC14A reduces actin dynamics to restrict tumor malignancy.

Sperm penetration of immature and maturing oocytes does not affect phosphorylation of mitogen-activated protein kinase in pigs

2003 ◽  
Vol 15 (7) ◽  
pp. 383 ◽  
Author(s):  
H. M. Quan ◽  
X. Q. Meng ◽  
Y. Hou ◽  
Q. Y. Sun
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Progression ◽  
Germinal Vesicle ◽  
Mitogen Activated Protein Kinase ◽  
Cycle Progression ◽  
Mapk Phosphorylation ◽  
Mitogen Activated Protein ◽  
Sperm Penetration

Pig oocytes cultured in vitro for 0, 25, 33 and 44 h were inseminated by frozen–thawed ejaculated sperm. At specified times after insemination, sperm penetration, cell cycle progression and mitogen-activated protein kinase (MAPK) phosphorylation were evaluated. It was shown that: (1) oocytes at various maturational stages could be penetrated by sperm; (2) sperm penetration did not affect meiotic cell cycle progression; (3) sperm penetration of germinal vesicle (GV) oocytes and maturing oocytes did not alter MAPK phosphorylation; and (4) when premetaphase I (pre-MI) and metaphase I (MI) oocytes, in which MAPK was activated, were fertilised, no evident MAPK dephosphorylation was detected as in metaphase II oocytes. The data suggest that sperm penetration before oocyte maturation does not affect MAPK phosphorylation and that the machinery inactivating MAPK upon fertilisation is not developed in maturing (pre-MI to MI) oocytes.

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