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Phosphatase Activation by Epidermal Growth Factor Family Ligands Regulates Extracellular Regulated Kinase Signaling in Undifferentiated Hen Granulosa Cells

Department of Biological Sciences, The University of Notre Dame, Notre Dame, Indiana 46556

Address all correspondence and requests for reprints to: A. L. Johnson, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556. E-mail: johnson.128{at}nd.edu.

Previous work has demonstrated that epidermal growth factor family ligands, signaling through the MAPK/ERK pathway, prevent hen granulosa cell differentiation, in vitro, even in the presence of factors that promote differentiation (e.g. TGFß and FSH). The working hypothesis is that a release from tonic inhibitory ERK signaling is prerequisite for the initiation of hen granulosa cell differentiation. Initial results demonstrate that the ERK signaling pathway is desensitized after treatment with TGF or betacellulin. Thus, studies were conducted to evaluate a role for MAPK phosphatases in the termination of ERK signaling in undifferentiated granulosa cells. Subsequent to ligand-induced translocation of ERK to the nucleus, de novo transcription and translation of one or more protein tyrosine or dual-specificity phosphatases results in dephosphorylation and localization of inactivated ERK within the nucleus. RT-PCR amplification reveals expression of the MAPK-selective phosphatases (MKP), MKP-1, -3, and dual-specificity phosphatase 5, in granulosa cells. TGF induces expression (within 3 h) of mRNA encoding the ERK-selective nuclear phosphatase, dual-specificity phosphatase 5, and subsequently (by 20 h) induces mRNA encoding the cytoplasmic phosphatase, MKP-3. Increased expression of phosphatases is associated with the intracellular localization and dephosphorylation of ERK and is inhibited by the selective ERK inhibitor, U0126. In turn, regulation of phosphatase activity occurs via the ubiquitin-proteasome degradation pathway because treatment of cells with the proteasome inhibitor, Z-LLF-CHO, markedly promotes ERK dephosphorylation. These data provide direct evidence for ERK-mediated negative feedback due to regulation of phosphatase activity in undifferentiated granulosa cells.

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