Cellular Functions of Mitogen-activated Protein Kinases and Protein Tyrosine Phosphatases in Ovarian Granulosa Cells

Abstract

Abstract.A number of endocrine and paracrine factors regulate the follicular growth and atresia, which are closely associated with granulosa cell survival and apoptosis. However, the molecular mechanisms underlying the intracellular events induced by these factors are poorly understood. Here, we describe the correlation of mitogen-activated protein kinase (MAPK) activities with granulosa cell survival and apoptosis, and the cellular functions of protein tyrosine phosphatases (PTPs) in these cells based on our recent data. MAPKs play key roles in various cellular responses because numerous extracellular stimuli are integrated into MAPKs. The protein phospho-Tyr level regulated by protein tyrosine kinases (PTKs) and PTPs is a major control mechanism for processes as diverse as cell survival, proliferation, differentiation, and metabolism. Although PTKs are critically involved in granulosa cell survival and proliferation, there are no reports indicating the roles of PTPs in the ovary except for ours. Information about MAPKs and PTPs in these cells will provide a basis for the understanding of the molecular mechanisms controlling the fate of follicles. Key words: Mitogen-activated protein kinase (MAPK), Protein tyrosine phosphatase (PTP), Granulosa cell, Apoptosis, Adenovirus (J. Reprod. Dev. 50: [47][48][49][50][51][52][53][54][55] 2004) ver 99% of ovarian follicles in mammals undergo a degenerative process called atresia, which is characterized by granulosa cell apoptosis [1,2]. In contrast, only a few follicles mature and reach ovulation under the cyclic gonadotropin stimulation. The selection of granulosa cell apoptosis or survival is a critical process in determining the fate of follicles. To date, a number of endocrine and paracrine factors have been shown as survival or apoptosis-inducing factors for these cells in vivo and in vitro [1,2], but the molecular mechanisms underlying the induced intracellular events are poorly understood. In this review, we describe the correlation of mitogenactivated protein kinase (MAPK) activities with granulosa cell survival and apoptosis, and the cellular functions of protein tyrosine phosphatases (PTPs) in granulosa cells based on our recent data [3][4][5]. Both MAPKs and PTPs are considered important regulators for granulosa cell survival, proliferation, differentiation and apoptosis as they are in other types of cells. Correlation of MAPK Activities with Granulosa Cell Survival and Apoptosis MAPK familyA vast number of extracellular stimuli are integrated into MAPKs that conversely affect many of the signaling pathways induced by these stimuli.

Protein kinases and ovarian functions

“…4). Effect of pharmacological activators or blockers of PKs showed, that PKA, PKG, MAPKs, PI3K/Akt, CDKs, TKs, and ALK can both promote (in some cases also suppress) ovarian granulosa cell proliferation (Makarevich et al, , 2004bTamura et al, 2004;Sirotkin andGrossmann, 2003, 2006;Wang and Tsang, 2007), although the ability of TK-dependent intracellular signaling to stimulate ovarian folliculogenesis and ovulation is reported too (Matousek et al, 1999). The cAMP/PKAdependent intracellular mechanisms can either inhibit (Peluso, 2006;Graves and Lawrence, 1996;Hsueh et al, 1996;Hillier and Tetsuka, 1997), stimulate (Cheadle et al, 2008;Viegas et al, 2008) or not influence (Dupont et al, 2008) follicular cell proliferation, but other PKs are involved predominantly in promotion of ovarian cell cycle.…”

“…Regulators of PKA, PKG, MAPKs, PI3K, Akt, CDKs, TKs, and ALK affecting ovarian follicular cell proliferation (Peluso, 2006;Graves and Lawrence, 1996;Hsueh et al, 1996;Hillier and Tetsuka, 1997;Matousek et al, 1999;Makarevich et al, 2002Makarevich et al, , 2004bTamura et al, 2004;Sirotkin andGrossmann, 2003, 2006;Wang and Tsang, 2007;Dupont et al, 2008;Cheadle et al, 2008;Viegas et al, 2008) can be used for stimulation of ovarian folliculogenesis, increase in number of ovulations and, perhaps, for control of hypogonadism, PCOS and other ovarian disorders associated with impaired follicular growth.…”

Thyroid hormones induce cell proliferation and survival in ovarian granulosa cells COV434

“…Nonetheless, many reports have indicated the MAPK pathway as a good mediator of the cellular survival in granulosa cells (Tamura et al, 2004). Thyroid hormones have been related to both the MAPK and the PI3K pathways.…”

Inhibition of MAPK by Prolactin Signaling through the Short Form of Its Receptor in the Ovary and Decidua

“…However, this activation did not occur with PRL but only in response to S179D PRL, a molecular mimic of the phosphorylated form of PRL. Activation of ERK1/2 by PRL/PRL-RS may be unique to The MAPK family has a central role in various cellular responses including cell proliferation, differentiation, survival, and apoptosis (42,43). Recently, it was shown that MAPK critically regulate the fate of ovarian granulosa cells (25,42).…”

“…Activation of ERK1/2 by PRL/PRL-RS may be unique to The MAPK family has a central role in various cellular responses including cell proliferation, differentiation, survival, and apoptosis (42,43). Recently, it was shown that MAPK critically regulate the fate of ovarian granulosa cells (25,42). Activation of p38 MAPK by FSH leads to phosphorylation of HSP-27 in granulosa cells, resulting in cell rounding and aggregation promoting microfilament reorganization and stabilization (44), suggesting a role in granulosa cell survival.…”