NCBI Summary:
The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product inactivates ERK1, is expressed in a variety of tissues with the highest levels in pancreas and brain, and is localized in the nucleus. [provided by RefSeq, Jul 2008]
General function
Enzyme
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Comment
Expression regulated by
Growth Factors/ cytokines, FGF2
Comment
Regulation of Dual Specificity Phosphatases by Fibroblast Growth Factor signaling pathways in bovine granulosa cells. Relav L et al. (2021) Controling the duration and amplitude of mitogen activated protein kinase (MAPK) signaling is an important element in deciding cell fate. One group of intracellular negative regulators of MAPK activity is a subfamily of the dual specificity phosphatase (DUSP) superfamily, of which up to 16 members have been described in ovarian granulosa cells. Growth factors stimulate proliferation of granulosa cells through MAPK, PKC and AKT pathways, although it is not known which pathways control DUSP expression in these cells. The aim of the present study was to identify which pathways are involved in the regulation of DUSP expression using a well-established serum-free culture system for bovine granulosa cells. Stimulation of cells with FGF2 increased DUSP1, DUSP5 and DUSP6 mRNA abundance in a time and dose-dependent manner, and increased DUSP5 and DUSP6 protein accumulation. None of the other eleven DUSP measured were regulated by FGF2. Pharmacological inhibition of MAPK3/1 signaling decreased FGF2-stimulated DUSP1, DUSP5 and DUSP6 mRNA levels (p < 0.05) whereas inhibition of PKC did not affect the expression of these three DUSPs. Abundance of FGF2-dependent DUSP6 mRNA was reduced by inhibition of PLC or by chelating calcium, but DUSP5 mRNA abundance was not affected. Abundance of basal DUSP1 and DUSP6, but not DUSP5, mRNA was increased by the addition of the calcium ionophore A23187. We conclude that FGF2 stimulation of DUSP5 abundance requires MAPK3/1 whereas DUSP6 mRNA accumulation is dependent on calcium signaling as well as MAPK3/1 activation, suggesting complex regulation of physiologically important DUSPs in the follicle.//////////////////
Ovarian localization
Granulosa
Comment
COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) ACCELERATES TERMINATION OF FSH-INDUCED ERK1/2 AND AKT ACTIVATION BY REGULATING THE EXPRESSION AND DEGRADATION OF SPECIFIC MAP KINASE PHOSPHATASES IN BOVINE GRANULOSA CELLS. Sen A et al. Pleiotropic actions of CART are well described in the central nervous system and periphery but the intracellular mechanisms mediating biological actions of CART are poorly understood. Although CART is not expressed in mouse ovaries, we have previously established CART as a novel intracellular regulator of estradiol production in bovine granulosa cells. We demonstrated that inhibitory actions of CART on estradiol production are mediated through inhibition of FSH-induced cAMP accumulation, Ca(2+) influx and aromatase mRNA expression via a Go/i dependent pathway. We also reported that FSH-induced estradiol production is dependent on Erk1/2 and Akt signaling and CART may regulate other signaling proteins downstream of cAMP essential for estradiol production. Here, we demonstrate that CART is a potent inhibitor of FSH-stimulated Erk1/2 and Akt signaling and the mechanisms involved. Transient CART stimulation of bovine granulosa cells shortens the duration of FSH-induced Erk1/2 and Akt signaling while a prolonged (24 h) CART treatment blocks Erk1/2 and Akt activation in response to FSH. This CART-induced accelerated termination of Erk1/2 and Akt signaling is mediated both by induced expression and impaired ubiquitin-mediated proteasome degradation of dual specific phosphatase 5 (DUSP5) and protein phosphatase 2A (PP2A). Results also support existence of a negative feedback loop where CART via a Go/i-MEK dependent pathway activates Erk1/2 and the latter induces DUSP5 expression. Moreover, siRNA mediated ablation of DUSP5 and/or PP2A prevents the CART-induced early termination of Erk1/2 and Akt signaling. Results provide novel insight into the intracellular mechanism of action of CART in regulation of FSH-induced MAP kinase signaling.