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J. Biol. Chem., Vol. 283, Issue 21, 14479-14489, May 23, 2008

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Identification of Extracellular Signal-regulated Kinase 1/2 and p38 MAPK as Regulators of Human Sperm Motility and Acrosome Reaction and as Predictors of Poor Spermatozoan Quality^*

Tal Almog¹, Shlomi Lazar¹, Nachum Reiss, Nir Etkovitz, Eyal Milch^¶, Nir Rahamim, Masha Dobkin-Bekman, Ronit Rotem, Moshe Kalina^||, Jacob Ramon^¶, Arieh Raziel^**, Haim Brietbart, Rony Seger, and Zvi Naor²

From the Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, the ^¶Department of Urology, The Chaim Sheba Medical Center at Tel Hashomer, Tel Hashomer, Ramat-Gan 52621, the ^||Department of Cell Biology and Histology and ^**Male Infertility and In Vitro Fertilization Unit, Assaf Harofeh Medical Center, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, and the Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel

Mature spermatozoa acquire progressive motility only after ejaculation. Their journey in the female reproductive tract also includes suppression of progressive motility, reactivation, capacitation, and hyperactivation of motility (whiplash), the mechanisms of which are obscure. MAPKs are key regulatory enzymes in cell signaling, participating in diverse cellular functions such as growth, differentiation, stress, and apoptosis. Here we report that ERK1/2 and p38 MAPK are primarily localized to the tail of mature human spermatozoa. Surprisingly, c-Jun N-terminal kinase 1/2, which is thought to be ubiquitously expressed, could not be detected in mature human spermatozoa. ERK1/2 stimulation is downstream to protein kinase C (PKC) activation, which is also present in the human sperm tail (PKCβI and PKC). ERK1/2 stimulates and p38 inhibits forward and hyperactivated motility, respectively. Both ERK1/2 and p38 MAPK are involved in the acrosome reaction. Using a proteomic approach, we identified ARHGAP6, a RhoGAP, as an ERK substrate in PMA-stimulated human spermatozoa. Inverse correlation was obtained between the relative expression level of ERK1 or the relative activation level of p38 and sperm motility, forward progression motility, sperm morphology, and viability. Therefore, increased expression of ERK1 and activated p38 can predict poor human sperm quality.

Received for publication, December 26, 2007 , and in revised form, March 25, 2008.

^* This work was supported by the United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Program of Research Development and Research Training in Human Reproduction, World Health Organization, Project A15118 (2001) and from the Ministry of Science and Technology Grant NOFAR (2003). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental videos 1 and 2.

¹ Both authors contributed equally to this work.

This paper is dedicated to the memory of Prof. Moshe Kalina, who died in 2004.

² To whom correspondence should be addressed. Fax: 972-3-6406834; E-mail: zvin{at}tauex.tau.ac.il.

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