Identification and characterization of SSTK, a serine/threonine protein kinase essential for male fertility

被引:102
作者
Spiridonov, NA
Wong, L
Zerfas, PM
Starost, MF
Pack, SD
Paweletz, CP
Johnson, GR
机构
[1] US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA
[2] Natl Inst Allergy & Infect Dis, Lab Immunopathol, NIH, Bethesda, MD 20892 USA
[3] Univ Hlth Sci, Uniformed Serv, Dept Anat Physiol & Genet, Inst Mol Med, Bethesda, MD 20814 USA
关键词
D O I
10.1128/MCB.25.10.4250-4261.2005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Here we describe and characterize a small serine/threonine kinase (SSTK) which consists solely of the Nand Globes of a protein kinase catalytic domain. SSTK protein is highly conserved among mammals, and no close homologues were found in the genomes of nonmammalian organisms. SSTK specifically interacts with HSP90-1 beta, HSC70, and HSP70 proteins, and this association appears to be required for SSTK kinase activity. The SSTK transcript was most abundant in human and mouse testes but was also detected in all human tissues tested. In the mouse testis, SSTK protein was localized to the heads of elongating spermatids. Targeted deletion of the SSTK gene in mice resulted in male sterility due to profound impairment in motility and morphology of spermatozoa. A defect in DNA condensation in SSTK null mutants occurred in elongating spermatids at a step in spermiogenesis coincident with chromatin displacement of histones by transition proteins. SSTK phosphorylated histones H1, H2A, H2AX, and H3 but not H2B or H4 or transition protein I in vitro. These results demonstrate that SSTK is required for proper postmeiotic chromatin remodeling and male fertility. Abnormal sperm chromatin condensation is common in sterile men, and our results may provide insight into the molecular mechanisms underlying certain human infertility disorders.
引用
收藏
页码:4250 / 4261
页数:12
相关论文
共 38 条
[1]   Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [J].
Altschul, SF ;
Madden, TL ;
Schaffer, AA ;
Zhang, JH ;
Zhang, Z ;
Miller, W ;
Lipman, DJ .
NUCLEIC ACIDS RESEARCH, 1997, 25 (17) :3389-3402
[2]   Histone variants and histone modifications:: A structural perspective [J].
Ausió, J ;
Abbott, DW ;
Wang, XY ;
Moore, SC .
BIOCHEMISTRY AND CELL BIOLOGY, 2001, 79 (06) :693-708
[3]   HOW MAP KINASES ARE REGULATED [J].
COBB, MH ;
GOLDSMITH, EJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (25) :14843-14846
[4]   A common requirement for the catalytic activity and both SH2 domains of SHP-2 in mitogen-activated protein (MAP) kinase activation by the ErbB family of receptors - A specific role for SHP-2 in MAP, but not c-jun amino-terminal kinase activation [J].
Deb, TB ;
Wong, L ;
Salomon, DS ;
Zhou, GC ;
Dixon, JE ;
Gutkind, JS ;
Thompson, SA ;
Johnson, GR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (27) :16643-16646
[5]   Epidermal growth factor (EGF) receptor kinase-independent signaling by EGF [J].
Deb, TB ;
Su, L ;
Wong, L ;
Bonvini, E ;
Wells, A ;
David, M ;
Johnson, GR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (18) :15554-15560
[6]   Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility [J].
Dix, DJ ;
Allen, JW ;
Collins, BW ;
Mori, C ;
Nakamura, N ;
PoormanAllen, P ;
Goulding, EH ;
Eddy, EM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (08) :3264-3268
[7]   Role of heat shock protein HSP70-2 in spermatogenesis [J].
Eddy, EM .
REVIEWS OF REPRODUCTION, 1999, 4 (01) :23-30
[8]   Spermatogenesis of mice lacking CK2α′:: Failure of germ cell survival and characteristic modifications of the spermatid nucleus [J].
Escalier, D ;
Silvius, D ;
Xu, X .
MOLECULAR REPRODUCTION AND DEVELOPMENT, 2003, 66 (02) :190-201
[9]   Ligand regulates epidermal growth factor receptor kinase specificity -: Activation increases preference for GAB1 and SHC versus autophosphorylation sites [J].
Fan, YX ;
Wong, L ;
Deb, TB ;
Johnson, GR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) :38143-38150
[10]   SYNTHESIS AND PROCESSING OF MAMMALIAN PROTAMINES AND TRANSITION PROTEINS [J].
GREEN, GR ;
BALHORN, R ;
POCCIA, DL ;
HECHT, NB .
MOLECULAR REPRODUCTION AND DEVELOPMENT, 1994, 37 (03) :255-263