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.
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 (PKCbetaI and PKCepsilon). 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.
Almog
Tal
T
Department of Biochemistry, George S Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
Lazar
Shlomi
S
Reiss
Nachum
N
Etkovitz
Nir
N
Milch
Eyal
E
Rahamim
Nir
N
Dobkin-Bekman
Masha
M
Rotem
Ronit
R
Kalina
Moshe
M
Ramon
Jacob
J
Raziel
Arieh
A
Breitbart
Haim
H
Brietbart
Haim
H
Seger
Rony
R
Naor
Zvi
Z
D020101:Acrosome Reaction; D000595:Amino Acid Sequence; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048053:Mitogen-Activated Protein Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D010703:Phorbol Esters / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013081:Sperm Motility; D013094:Spermatozoa / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C109971:ARHGAP6 protein, human; D020690:GTPase-Activating Proteins; D010703:Phorbol Esters; D047428:Protein Kinase Inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D048053:Mitogen-Activated Protein Kinase 6; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins