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Journal of Molecular Endocrinology (2007) 38 137-146    DOI: 10.1677/jme.1.02027
© 2007 Society for Endocrinology

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Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development

Lian Liu1,6, Singareddy Rajareddy1, Pradeep Reddy1, Krishna Jagarlamudi1, Chun Du1, Yan Shen1, Yongzhi Guo1, Karin Boman2, Eva Lundin3, Ulrika Ottander4, Gunnar Selstam5 and Kui Liu1

1 Departments of Medical Biochemistry and Biophysics,
2 Radiation Sciences,
3 Medical Biosciences/Pathology,
4 Clinical Science/Obstetrics and Gynecology,
5 Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden
6 Qilu Hospital, Shandong University, Jinan, 250012 Shandong, China

(Requests for offprints should be addressed to K Liu; Email: kui.liu{at}medchem.umu.se)

(L Liu, S Rajareddy and P Reddy contributed equally to this work)

Communication between mammalian oocytes and their surrounding granulosa cells through the Kit–Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL–Kit–PI3 kinase (PI3K)–Akt–Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3{alpha} and GSK-3ß, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3{alpha} and GSK-3ß in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3{alpha} and GSK-3ß. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit–PI3K–Akt–GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.




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