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

Abstract

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 PKCϵ). 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. 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 PKCϵ). 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. Sperm are immotile in the testes and they acquire progressive motility after ejaculation. They cross the uterine cervix, undergo suppression of progressive motility, become capacitated (capable to fertilize), including resumption of another form of motility, hyperactivation, bind the egg, undergo the acrosome reaction, and fertilize it (1Garbers D.L. Nature. 2001; 413: 579-582Crossref PubMed Scopus (18) Google Scholar, 2Eisenbach M. Giojalas L.C. Nat. Rev. Mol. Cell Biol. 2006; 7: 276-285Crossref PubMed Scopus (391) Google Scholar). Relatively little is known about the molecular mechanisms that mediate spermatozoan functions in general and the various forms of motility in particular (1Garbers D.L. Nature. 2001; 413: 579-582Crossref PubMed Scopus (18) Google Scholar, 2Eisenbach M. Giojalas L.C. Nat. Rev. Mol. Cell Biol. 2006; 7: 276-285Crossref PubMed Scopus (391) Google Scholar). MAPK 3The abbreviations used are: MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; OAG, 1-oleoyl-2-acetylglycerol; JNK, c-Jun N-terminal kinase; GPCR, G-protein-coupled receptor; MBP, myelin basic protein; CASA, computer-aided sperm analysis; SM, sperm motility; FPM, forward progression motility; ROC, receiver operating characteristic; AUC, area under the curve; BAPTA/AM, 2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester); PBS, phosphate-buffered saline; FITC, fluorescein isothiocyanate; BSA, bovine serum albumin; MALDI-TOF, matrix-assisted laser desorption ionization time-of-flight; PMA, phorbol myristoyl acetate. cascades play a crucial role in metazoan development, including fate determination, differentiation, proliferation, survival, migration, growth, cell cycle progression, and apoptosis (3Seger R. Krebs E.G. FASEB J. 1995; 9: 726-735Crossref PubMed Scopus (3218) Google Scholar, 4Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar, 5Pearson G. Robinson F. Beers Gibson T. Xu B.E. Karandikar M. Berman K. Cobb M.H. Endocr. Rev. 2001; 22: 153-183Crossref PubMed Scopus (3564) Google Scholar, 6Murphy L.O. Blenis J. Trends Biochem. Sci. 2006; 31: 268-275Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 7Yoon S. Seger R. Growth Factors. 2006; 24: 21-44Crossref PubMed Google Scholar). MAPK cascades consist of several tiers of protein kinases that activate each other by sequential phosphorylation. Four major MAPK cascades are known in mammals: ERK1–2, JNK 1–3, p38 α–δ, and ERK5 (big MAPK; BMK) (3Seger R. Krebs E.G. FASEB J. 1995; 9: 726-735Crossref PubMed Scopus (3218) Google Scholar, 4Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar, 5Pearson G. Robinson F. Beers Gibson T. Xu B.E. Karandikar M. Berman K. Cobb M.H. Endocr. Rev. 2001; 22: 153-183Crossref PubMed Scopus (3564) Google Scholar, 6Murphy L.O. Blenis J. Trends Biochem. Sci. 2006; 31: 268-275Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 7Yoon S. Seger R. Growth Factors. 2006; 24: 21-44Crossref PubMed Google Scholar). Activation of MAPK is initiated by activation of MAP3Ks by the small G-proteins of the Ras family (e.g. Ras, CDC42, and Rac), followed by sequential activation of MAPKKs and MAPKs. The prototypic ERK cascade is activated by growth factors, mitogens, and G-protein-coupled receptors (GPCR) and consists of Rafs (MAP3K), MEK1/2, ERK1/2, and several MAPK-activating protein kinases (MAPKAPKs). The stress-activated protein kinases are now known as JNK and p38 MAPK. Both are initiated by stress stimuli, GPCRs, inflammatory cytokines, and growth factors. JNK1–3 consists of a sequential activation of Rac1/Cdc42, mixed lineage kinases as MAP3Ks, MAPK kinases 4 and 7, and JNK1–3. The p38 MAPK cascade is composed of sequential activation of MAP3Ks, MKK3/4/6, p38α–δ, and several MAPKAPKs (3Seger R. Krebs E.G. FASEB J. 1995; 9: 726-735Crossref PubMed Scopus (3218) Google Scholar, 4Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (692) Google Scholar, 5Pearson G. Robinson F. Beers Gibson T. Xu B.E. Karandikar M. Berman K. Cobb M.H. Endocr. Rev. 2001; 22: 153-183Crossref PubMed Scopus (3564) Google Scholar, 6Murphy L.O. Blenis J. Trends Biochem. Sci. 2006; 31: 268-275Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 7Yoon S. Seger R. Growth Factors. 2006; 24: 21-44Crossref PubMed Google Scholar). Mature spermatozoa are fully differentiated cells that lack active transcriptional machinery. Hence, it is of great interest to investigate whether ejaculated human spermatozoa express and utilize MAPKs, which specialize in growth, differentiation, and stress. Because spermatozoa lack those functions, the studies might point to novel functions mediated by MAPKs. During spermatogenesis, MAPKs mediate cell division, differentiation, survival, adhesion, and death (8Wong C.H. Cheng C.Y. Dev. Biol. 2005; 286: 1-15Crossref PubMed Scopus (99) Google Scholar). MAPKs were reported to play a role during meiotic progression of mouse spermatocytes (9Sette C. Barchi M. Bianchini A. Conti M. Rossi P. Geremia R. J. Biol. Chem. 1999; 274: 33571-33579Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 10Lu Q. Sun Q.Y. Breitbart H. Chen D.Y. Arch. Androl. 1999; 43: 55-66Crossref PubMed Scopus (47) Google Scholar, 11Rhee K. Wolgemuth D.J. Development (Camb.). 1997; 124: 2167-2177PubMed Google Scholar, 12Di Agostino S. Botti F. Di Carlo A. Sette C. Geremia R. Reproduction. 2004; 128: 25-32Crossref PubMed Scopus (27) Google Scholar) and in adhesion function at the Sertoli-germ cell interface (8Wong C.H. Cheng C.Y. Dev. Biol. 2005; 286: 1-15Crossref PubMed Scopus (99) Google Scholar). On the other hand, the role of MAPK in mature mammalian spermatozoan motility, capacitation, and acrosome reaction is limited and controversial as detailed below (10Lu Q. Sun Q.Y. Breitbart H. Chen D.Y. Arch. Androl. 1999; 43: 55-66Crossref PubMed Scopus (47) Google Scholar, 13Baldi E. Luconi M. Bonaccorsi L. Forti G. Front. Biosci. 1998; 3: D1051-D1059Crossref PubMed Google Scholar, 14de Lamirande E. Gagnon C. Mol. Hum. Reprod. 2002; 8: 124-135Crossref PubMed Scopus (143) Google Scholar, 15du Plessis S.S. Page C. Franken D.R. Andrologia. 2002; 34: 55-59PubMed Google Scholar, 16Weidinger S. Mayerhofer A. Kunz L. Albrecht M. Sbornik M. Wunn E. Hollweck R. Ring J. Kohn F.M. Hum. Reprod. 2005; 20: 456-461Crossref PubMed Scopus (29) Google Scholar, 17Chen W.Y. Ni Y. Pan Y.M. Shi Q.X. Yuan Y.Y. Chen A.J. Mao L.Z. Yu S.Q. Roldan E.R. FEBS Lett. 2005; 579: 4692-4700Crossref PubMed Scopus (28) Google Scholar). In particular the role of JNK and p38 MAPK in ejaculated spermatozoa is not known (8Wong C.H. Cheng C.Y. Dev. Biol. 2005; 286: 1-15Crossref PubMed Scopus (99) Google Scholar). We therefore inquired whether ejaculated mature human spermatozoa express and utilize the various MAPKs (ERK, JNK, and p38) (6Murphy L.O. Blenis J. Trends Biochem. Sci. 2006; 31: 268-275Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 7Yoon S. Seger R. Growth Factors. 2006; 24: 21-44Crossref PubMed Google Scholar), which may orchestrate the fine-tuning of sperm motility. Our results indicate that ERK1/2 and p38 MAPK, but not JNK1/2, are expressed in the tail of ejaculated human spermatozoa. Activation of ERK1/2 is downstream to PKC activation, and two of its isoforms (PKCβI and PKCϵ) are also present in the human sperm tail R. M. J. Breitbart H. PubMed Scopus Google Scholar). Surprisingly, we that ERK stimulates and p38 MAPK inhibits forward and hyperactivated motility, respectively. We also that ERK1/2 and p38 MAPK are involved in acrosome reaction. Using a proteomic approach, we identified ARHGAP6, a RhoGAP, as an ERK substrate in PMA-stimulated human spermatozoa. we that correlation between ERK1 and and sperm motility, forward progression motility, sperm morphology, and viability. increased expression of ERK1 and activated MAPK could predict poor human sperm quality. of was obtained sperm motility, and to the of and Scholar) or the or the in The human was at Sperm was bovine serum and the R. M. Sci. S. A. PubMed Scopus Google Scholar). or were or the PKC or the and or the p38 and or the and to the as in the sperm were by The cells were and by followed by R. M. Sci. S. A. PubMed Scopus Google Scholar). The cells were the MAPK (ERK, JNK, and p38) or MEK1/2, or at 4 were in the cells were at the as R. M. Sci. S. A. PubMed Scopus Google Scholar). was in and in of the MAPK was by of the and by the of the an of the MAPK the the studies were obtained sperm were in in at M. R. R. J. 1995; 43: PubMed Scopus Google Scholar). the were in and in The cells were not of of in were and was as M. R. R. J. 1995; 43: PubMed Scopus Google Scholar). were in in PBS, and in the were at 4 in the were or and the were and was and were a were and and to were PBS, in was in were or PBS, and a or a were a laser Activation of MAPK and human spermatozoa were as and PMA, or other as and cell was used the cells were by at at and and the were at The were at 4 were in a of of and The were and 4 The which were and each were followed by mouse MAPKs (ERK, JNK, and p38) or mouse MAPKs were detected the various general MAPKs as a The were or or The were and the was by the (ERK, JNK, and p38) was to the the MAPK S. Seger R. 2004; PubMed Scopus Google Scholar). of ERK, activated human was active in as Cobb M.H. 2001; PubMed Scopus Google Scholar). The were in at to an of and was an 4 were or to the Cell and cells were in bovine serum in at were in to and were 4 of the and as the was and the cells were and The was to an protein to protein by in 4 and were in and were to in phosphorylation. In to was mixed ERK to The reaction was to the reaction in a of and at The reaction was by of and the were of by ERK was as a of Sperm motility was R. M. Sci. S. A. PubMed Scopus Google Scholar) or by Sperm which was also used to hyperactivation S.S. Reproduction. 2001; PubMed Scopus Google Scholar). were as of of Sperm of sperm was sperm which is a of to the cells were capacitated at and in R. M. Sci. S. A. PubMed Scopus Google Scholar). The were the of and was another the of an of the sperm was and to The sperm were by at and at and at and each at cells in were the were those or were The of was by of between MAPK and Sperm spermatozoa the were MAPK and as and sperm motility forward progression motility morphology, and the of and Scholar). The were obtained correlation was used to to and motility and was used was used was MAPK receiver operating M.H. G. Chem. PubMed Scopus Google Scholar) was used motility and We the area under the which the of the and a was two or were expressed as were to of and and was are detailed in the ERK1/2 its cascade and p38 MAPK, but not JNK, were identified in the tail of mature ejaculated human spermatozoa by The ERK cascade and p38 were localized in the and the and of the in the was the that ERK1/2 was localized to the that ERK1/2 is to the p38 is primarily localized to the expression of ERK1/2 and p38 in human spermatozoa. spermatozoa were and are ERK1/2 and p38 in and and are in C and G. are in and H. the of ERK1/2 was the p38 to also in the and the tail indicate We identified the of active ERK1/2 and p38 in human ejaculated spermatozoa by and it the known PMA-stimulated MAPK in the mouse cells S. Seger R. 2004; PubMed Scopus Google Scholar) spermatozoa express which was by or by the general as an of the of PKC, and the activation of The reported to activate human sperm ERK M. C. T. Forti G. E. Mol. Hum. Reprod. 1998; PubMed Scopus Google Scholar), p38 MAPK in its form was in cells but was present in spermatozoa. We could not activation of by PMA, a of in cells The that sperm p38 MAPK is fully p38 MAPK is by that isoforms G. Robinson F. Beers Gibson T. Xu B.E. Karandikar M. Berman K. Cobb M.H. Endocr. Rev. 2001; 22: 153-183Crossref PubMed Scopus (3564) Google Scholar), and we could and is present in cells and is activated by but is in or spermatozoa. We spermatozoa in a to in R. M. Sci. S. A. PubMed Scopus Google Scholar). to the ERK1/2 in ERK activation by can be detected in and capacitated spermatozoa. activation by was to the and the of a cascade (6Murphy L.O. Blenis J. Trends Biochem. Sci. 2006; 31: 268-275Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 7Yoon S. Seger R. Growth Factors. 2006; 24: 21-44Crossref PubMed Google Scholar) in spermatozoa and the of the two in the studies The p38 to ERK signaling, an between p38 MAPK and ERK H. Shi M. L. S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The the activation of ERK1/2, that the was ERK activation by was to to or to in which activation of ERK by was by the ERK activation in human spermatozoa is to and to p38 and to the human sperm were the and the p38 and the PKC and was another Cell were and was as in are by are ERK activation is human spermatozoa were or various general and was and was as in is and are by are of spermatozoa motility the of and Scholar) the motility in In of spermatozoa motility the of and Scholar) the p38 motility we could sperm forward motility, spermatozoa motility by PMA, or the p38 or another p38 results were sperm of motility. We also forward and hyperactivated motility C and that the of sperm motility by the of human spermatozoa in in particular the is of limited Y. H. H. T. S. C. H. J. Reprod. 2001; PubMed Google Scholar, J. Androl. 2006; PubMed Scopus Google Scholar). increased forward and hyperactivated motility also The and and the forward and hyperactivated motility In as in the the p38 and forward and hyperactivated motility and the C and p38 and ERK1/2 are involved in sperm motility in an p38 forward and hyperactivated motility, ERK1/2 and forward and hyperactivated motility. the also stimulates ERK1/2 and forward and hyperactivated motility also the role of ERK1/2 in human spermatozoan of the ERK1/2 activation and forward and hyperactivated motility in ejaculated human spermatozoa. capacitated human spermatozoa were of or cell were ERK by an ERK was detected as a is and results were in two other and capacitated human spermatozoa were motility and hyperactivation of motility were are by are The role of ERK and p38 in the acrosome reaction that spermatozoa undergo in to fertilize the R. E. J. The of Reproduction. Scholar) was spermatozoa were PMA, a known of the acrosome reaction H. J. R. Biochem. J. 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We a proteomic to ERK in human spermatozoa. and cells were to followed by We that phosphorylation. major was and to and the identified protein was ARHGAP6, a we could now the results by spermatozoan can be in by myelin basic protein a known ERK substrate as a whether MAPK can be to human sperm we MAPK SM, FPM, morphology, and the of and Scholar). and p38 MAPK and only ERK1 and p38 correlation to the sperm that ERK1 and are sperm motility the of and Scholar) and forward progression motility the of and Scholar) which the of the and sperm to be a and sperm motility ERK1 is a forward progression motility Using a point of could motility and and forward progression motility and is and between MAPK and sperm the were SM, morphology, and viability. MAPK were as under The correlation between MAPK and sperm was after by correlation progression in a between MAPK and sperm of and of MAPK were obtained not progression motility in a of ERK1 and and motility forward progression under the under the is an of an of to in which the of is is an of an of to in which the of is in a We identified the and p38 MAPK in mature ejaculated human spermatozoa by and Surprisingly, we could not the other stress-activated MAPK, JNK by the We therefore that JNK may be involved in but not in mature spermatozoa. we that JNK expression is as it in L. T. and in the lack of expression of JNK in ejaculated spermatozoa is JNK is thought to be ubiquitously expressed M. T. T. M. Full Text PDF PubMed Scopus Google Scholar) and are C.Y. D.R. P. 1999; 22: Full Text Full Text PDF PubMed Scopus Google Scholar). We ERK and p38 MAPK in the of mature human and and R. M. Sci. S. A. 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ERK1 and to be and and SM, respectively. that and ERK1 could and sperm motility and Because ERK is involved in motility, and the of cellular ERK is in its a and a in its form the and the Because p38 is involved in motility, it is therefore that p38 or fully correlation to motility as the In we only and the of ERK1 sperm quality. MAPKs are thought to be at the level and not protein expression S. Seger R. Growth Factors. 2006; 24: 21-44Crossref PubMed Google Scholar). Our results a role ERK1 Mature spermatozoa are fully differentiated cells and not active transcriptional and ERK1 expression may during mature spermatozoa an active Y. Breitbart H. Dev. 2006; 20: PubMed Scopus Google we not the of ERK1 expression in mature spermatozoa various of are Y. J. K. Sci. S. A. PubMed Scopus Google Scholar), ERK1 are G. S. F. A. F. P. J. 1999; 286: PubMed Scopus Google Scholar). We that is the major of ERK1/2 activation in the sperm are S. M. S. L. S. J. J. L. J. Biol. 1999; 9: Full Text Full Text PDF PubMed Scopus Google Scholar), are S. M. P. R. J. Mol. Biol. PubMed Scopus Google Scholar). The of sperm and is of the in of sperm in P. S. A. J. P. A. Hum. Reprod. PubMed Scopus Google Scholar) and a general in are in the the mechanisms involved in sperm the mechanisms of its Our reported basic of human We a molecular the various forms of sperm motility Our might be to expression of ERK1/2 and p38 in the various forms of (e.g. MAPK and may be as a to sperm of or spermatozoa are used during reproductive ERK1 and MAPK can be as a spermatozoan Our studies might also the the of MAPK or as the of and and We and the and and the the sperm We K. and of and of the We also the in kinase and of We also the