Follicle-Stimulating Hormone (FSH)-dependent Regulation of Extracellular Regulated Kinase (ERK) Phosphorylation by the Mitogen-activated Protein (MAP) Kinase Phosphatase MKP3

Donaubauer, Elyse M.; Law, Nathan C.; Hunzicker-Dunn, Mary

doi:10.1074/jbc.m116.733972

Cited by 42 publications

(28 citation statements)

References 82 publications

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“…The proteasome inhibitor MG-132 prevents DUSP6 degradation, indicating the ubiquitin-proteasomal pathway is involved in this process. The degradation of DUSP6 protein is inversely correlated with the phosphorylation of ERK1/2 and indeed, as the DUSP6 inhibitor BCI enhances ERK1/2 phosphorylation, this protein phosphatase appears to be involved in regulating basal cytosolic ERK activation (Donaubauer et al, 2016 ). The specificity of BCI as an inhibitor of DUSP6 was first reported by studying the FGF-mediated increase in ERK signaling in zebrafish embryos (Molina et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…While DUSP6 expression is enhanced in some kinds of cancer (melanoma and glioma cells), suggesting it may be a tumor promotor (Messina et al, 2011 ; Li et al, 2012 ), its expression is dampened in other tumors where it may exert a role as a tumor suppressor, such as pancreatic invasive cancer, primary lung cancer and ovarian cancer (Furukawa et al, 2003 ; Chan et al, 2008 ; Okudela et al, 2009 ). Significantly, very little is known about the intrinsic regulation of DUSP6 in native tissues and its modulation by endogenous extracellular signals that activate receptor tyrosine kinases (RTKs) e.g., mitogens (Ham et al, 2015 ; Donaubauer et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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P2X7 Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling

Queipo

Gil-Redondo

Morente

et al. 2018

Front. Mol. Neurosci.

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Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play a central role in the intracellular signaling of P2X7 nucleotide receptors in neurons and glial cells. Fine spatio-temporal tuning of mitogen-activated protein (MAP) kinases is essential to regulate their biological activity. MAP kinase phosphatases (MKPs) are dual specificity protein phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues in MAP kinases. This study focuses on how DUSP, DUSP6/MKP3, a phosphatase specific for ERK1/2 is regulated by the P2X7 nucleotide receptor in cerebellar granule neurons and astrocytes. Stimulation with the specific P2X7 agonist, BzATP, or epidermal growth factor (EGF) (positive control for ERK activation) regulates the levels of DUSP6 in a time dependent manner. Both agonists promote a decline in DUSP6 protein, reaching minimal levels after 30 min yet recovering to basal levels after 1 h. The initial loss of protein occurs through proteasomal degradation, as confirmed in experiments with the proteasome inhibitor, MG-132. Studies carried out with Actinomycin D demonstrated that the enhanced transcription of the Dusp6 gene is responsible for recovering the DUSP6 protein levels. Interestingly, ERK1/2 proteins are involved in the biphasic regulation of the protein phosphatase, being required for both the degradation and the recovery phase. We show that direct Ser197 phosphorylation of DUSP6 by ERK1/2 proteins could be part of the mechanism regulating their cytosolic levels, at least in glial cells. Thus, the ERK1/2 activated by P2X7 receptors exerts positive feedback on these kinase’s own activity, promoting the degradation of one of their major inactivators in the cytosolic compartment, DUSP6, both in granule neurons and astrocytes. This feedback loop seems to function as a common universal mechanism to regulate ERK signaling in neural and non-neural cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

P2X7 Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling

Queipo

Gil-Redondo

Morente

et al. 2018

Front. Mol. Neurosci.

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“…Immunoblot, Immunoprecipitation, and Cell-free PKA Phosphorylation Assay-Following treatments, cells were collected and processed according to procedures described previously (31,77).…”

Section: Methodsmentioning

confidence: 99%

G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway

Law

White

Hunzicker-Dunn

2016

Journal of Biological Chemistry

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G protein-coupled receptors (GPCRs) activate PI3K/v-AKT thymoma viral oncoprotein (AKT) to regulate many cellular functions that promote cell survival, proliferation, and growth. However, the mechanism by which GPCRs activate PI3K/AKT remains poorly understood. We used ovarian preantral granulosa cells (GCs) to elucidate the mechanism by which the GPCR agonist FSH via PKA activates the PI3K/AKT cascade. Insulin-like growth factor 1 (IGF1) is secreted in an autocrine/paracrine manner by GCs and activates the IGF1 receptor (IGF1R) but, in the absence of FSH, fails to stimulate YXXM phosphorylation of IRS1 (insulin receptor substrate 1) required for PI3K/AKT activation. We show that PKA directly phosphorylates the protein phosphatase 1 (PP1) regulatory subunit myosin phosphatase targeting subunit 1 (MYPT1) to activate PP1 associated with the IGF1R-IRS1 complex. Activated PP1 is sufficient to dephosphorylate at least four IRS1 Ser residues, Ser, Ser, Ser, and Ser, and promotes IRS1 YXXM phosphorylation by the IGF1R to activate the PI3K/AKT cascade. Additional experiments indicate that this mechanism also occurs in breast cancer, thyroid, and preovulatory granulosa cells, suggesting that the PKA-dependent dephosphorylation of IRS1 Ser/Thr residues is a conserved mechanism by which GPCRs signal to activate the PI3K/AKT pathway downstream of the IGF1R.

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“…In particular, luteinizing hormone (LH) and follicle stimulating hormone (FSH) are the primary drivers of ovarian follicle growth and stimulators of the granulosa cells surrounding the developing oocyte [ 54 ]. A study performed on rat granulosa cells demonstrated that Dusp6 in the granulosa cells keeps ERK inactivated in the absence of FSH [ 55 ]. Once maturation is initiated by FSH, PKA is activated through cAMP to inhibit Dusp6, thereby allowing active pERK to accumulate and drive downstream genes promoting oocyte maturation and progression through the meiotic cell cycle [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

A parental requirement for dual-specificity phosphatase 6 in zebrafish

Maurer

Sagerström

2018

BMC Dev Biol

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BackgroundSignaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and are expressed in both embryonic and adult zebrafish, but their specific roles in embryogenesis remain to be fully understood.ResultsUsing CRISPR/Cas9 genome editing technology, we generated zebrafish lines harboring germ line deletions in dusp6 and dusp2. We do not detect any overt defects in dusp2 mutants, but we find that approximately 50% of offspring from homozygous dusp6 mutants do not proceed through embryonic development. These embryos are fertilized, but are unable to proceed past the first zygotic mitosis and stall at the 1-cell stage for several hours before dying by 10 h post fertilization. We demonstrate that dusp6 is expressed in gonads of both male and female zebrafish, suggesting that loss of dusp6 causes defects in germ cell production. Notably, the 50% of homozygous dusp6 mutants that complete the first cell division appear to progress through embryogenesis normally and give rise to fertile adults.ConclusionsThe fact that offspring of homozygous dusp6 mutants stall prior to activation of the zygotic genome, suggests that loss of dusp6 affects gametogenesis and/or parentally-directed early development. Further, since only approximately 50% of homozygous dusp6 mutants are affected, we postulate that ERK signaling is tightly regulated and that dusp6 is required to keep ERK signaling within a range that is permissive for proper embryogenesis. Lastly, since dusp6 is expressed throughout zebrafish embryogenesis, but dusp6 mutants do not exhibit defects after the first cell division, it is possible that other regulators of the ERK pathway compensate for loss of dusp6 at later stages.Electronic supplementary materialThe online version of this article (10.1186/s12861-018-0164-6) contains supplementary material, which is available to authorized users.

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Follicle-Stimulating Hormone (FSH)-dependent Regulation of Extracellular Regulated Kinase (ERK) Phosphorylation by the Mitogen-activated Protein (MAP) Kinase Phosphatase MKP3

Cited by 42 publications

References 82 publications

P2X7 Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling

P2X7 Nucleotide and EGF Receptors Exert Dual Modulation of the Dual-Specificity Phosphatase 6 (MKP-3) in Granule Neurons and Astrocytes, Contributing to Negative Feedback on ERK Signaling

G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway

A parental requirement for dual-specificity phosphatase 6 in zebrafish

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