Kinase Family TSSK

Kinase Classification: Group CAMK: Family TSSK

TSSK is a fast-evolving animal-specific family of testis-specific kinases.

Evolution

TSSK is found in most animals examined, with the exception of Trichoplax, most fishes, and amphibians. The family is fast-evolving: of 6 human members, two are found only in tetrapods (TSSK2 and TSSK3 are duplicates of TSSK1), TSSK5 is a pseudogene (it is functional in mouse), and TSSK1, TSSK4, TSSK5 and SSTK/TSSK6 all date back to pre-vertebrates. Xenopus lacks all TSSK, as do most fish, though zebrafish has an SSTK and stickleback has a TSSK1-like gene. Amphibians and fishes have a 'cystic' form of spermatogenesis, but it is not known if this functionally linked to their loss of TSSKs.

Domain Structure

TSSKs have a kinase domain with a very short N-terminal extension and a variable but still short C-terminal extension. All have a conserved activation loop threonine phosphorylation site (SQTFCGS in TSSK3), though only TSSK2 and TSSK3 are known to autophosphorylate and only TSSK3 requires the site for activity [1].

Function

TSSK1 and TSSK2 are formed by a tandem duplication and a dual knockout is infertile as a heterozygote [2]. TSSK6 knockout mice are also sterile [3], and SNPs in TSSK2 [4] TSSK4 [5] and TSSK6/SSTK [6] are associated with male infertility. Due to their largely testis-specific expression and their lack of close homologs, TSSKs have been suggested as an inhibitor target for contraception [7].

TSSK3 is expressed only in the interstitial Leydig cells, contrasting with the expression of TSSK1 and TSSK2 in late spermatids and sperm [8, 9]. TSSK1 and 2 also complex with each other and phosphorylate the amniote-specific protein, TSKS, while TSSK3 does neither. TSSK3 and TSSK5 in mouse were shown to interact with the receptor kinase TFGbR1, and with other members of the TGFb signaling pathways (SMAD4 for TSSK3 and SMURF1 for TSSK5) [10], and TGFb signaling is known to be active during spermatogenesis [11].

TSSK4 (originally named TSSK5) can bind to CREB by Y2H and can phosphorylate and activate CREB in both human and mouse cells [12, 13].

TSSK6/SSTK interacts with the HSP90 and HSP70 chaperone complexes, though a mammalian-specific protein, SIP [3, 14]. SSTK was expressed in the heads of elongating spermatids and the knockout had a defect DNA condensation at the point where histones are displaced from DNA. SSTK6 can phosphorylate histones in vitro, though this is a common substrate. Surviving SSTK-null sperm have defects in the actin cytoskeleton and fail to fuse with the egg [15].

Both Drosophila TSSKs, CG9222 and CG14305 are expressed in testis [16]. Neither has been characterized. CG9222 is one of 300 genes upregulated in migrating border cells during oogenesis, along with many muscle- and actin-related genes [17]. CG9222 was also found to interact with several protein by IP/MS [18], including several involved in mRNA splicing (Rsf1, Rbp1-like, SC35, CG17454, SF1, maybe CG4806, eap).

References

1. Hao Z, Jha KN, Kim YH, Vemuganti S, Westbrook VA, Chertihin O, Markgraf K, Flickinger CJ, Coppola M, Herr JC, and Visconti PE. Expression analysis of the human testis-specific serine/threonine kinase (TSSK) homologues. A TSSK member is present in the equatorial segment of human sperm. Mol Hum Reprod. 2004 Jun;10(6):433-44. DOI:10.1093/molehr/gah052 |
2. Xu B, Hao Z, Jha KN, Zhang Z, Urekar C, Digilio L, Pulido S, Strauss JF 3rd, Flickinger CJ, and Herr JC. Targeted deletion of Tssk1 and 2 causes male infertility due to haploinsufficiency. Dev Biol. 2008 Jul 15;319(2):211-22. DOI:10.1016/j.ydbio.2008.03.047 |
3. Spiridonov NA, Wong L, Zerfas PM, Starost MF, Pack SD, Paweletz CP, and Johnson GR. Identification and characterization of SSTK, a serine/threonine protein kinase essential for male fertility. Mol Cell Biol. 2005 May;25(10):4250-61. DOI:10.1128/MCB.25.10.4250-4261.2005 |
4. Zhang H, Su D, Yang Y, Zhang W, Liu Y, Bai G, Ma M, Ma Y, and Zhang S. Some single-nucleotide polymorphisms of the TSSK2 gene may be associated with human spermatogenesis impairment. J Androl. 2010 Jul-Aug;31(4):388-92. DOI:10.2164/jandrol.109.008466 |
5. Su D, Zhang W, Yang Y, Deng Y, Ma Y, Song H, and Zhang S. Mutation screening and association study of the TSSK4 Gene in Chinese infertile men with impaired spermatogenesis. J Androl. 2008 Jul-Aug;29(4):374-8. DOI:10.2164/jandrol.107.004598 |
6. Su D, Zhang W, Yang Y, Zhang H, Liu YQ, Bai G, Ma YX, Peng Y, and Zhang SZ. c.822+126T>G/C: a novel triallelic polymorphism of the TSSK6 gene associated with spermatogenic impairment in a Chinese population. Asian J Androl. 2010 Mar;12(2):234-9. DOI:10.1038/aja.2009.80 |
7. Xu B, Hao Z, Jha KN, Digilio L, Urekar C, Kim YH, Pulido S, Flickinger CJ, and Herr JC. Validation of a testis specific serine/threonine kinase [TSSK] family and the substrate of TSSK1 & 2, TSKS, as contraceptive targets. Soc Reprod Fertil Suppl. 2007;63:87-101.
8. Zuercher G, Rohrbach V, Andres AC, and Ziemiecki A. A novel member of the testis specific serine kinase family, tssk-3, expressed in the Leydig cells of sexually mature mice. Mech Dev. 2000 May;93(1-2):175-7. DOI:10.1016/s0925-4773(00)00255-0 |
9. Li Y, Sosnik J, Brassard L, Reese M, Spiridonov NA, Bates TC, Johnson GR, Anguita J, Visconti PE, and Salicioni AM. Expression and localization of five members of the testis-specific serine kinase (Tssk) family in mouse and human sperm and testis. Mol Hum Reprod. 2011 Jan;17(1):42-56. DOI:10.1093/molehr/gaq071 |
11. Dias VL, Rajpert-De Meyts E, McLachlan R, and Loveland KL. Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas. Reproduction. 2009 Nov;138(5):801-11. DOI:10.1530/REP-09-0206 |
12. Chen X, Lin G, Wei Y, Hexige S, Niu Y, Liu L, Yang C, and Yu L. TSSK5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates CREB at Ser-133, and stimulates the CRE/CREB responsive pathway. Biochem Biophys Res Commun. 2005 Aug 5;333(3):742-9. DOI:10.1016/j.bbrc.2005.05.157 |
13. Wei Y, Fu G, Hu H, Lin G, Yang J, Guo J, Zhu Q, and Yu L. Isolation and characterization of mouse testis specific serine/threonine kinase 5 possessing four alternatively spliced variants. J Biochem Mol Biol. 2007 Sep 30;40(5):749-56. DOI:10.5483/bmbrep.2007.40.5.749 |
18. Guruharsha KG, Rual JF, Zhai B, Mintseris J, Vaidya P, Vaidya N, Beekman C, Wong C, Rhee DY, Cenaj O, McKillip E, Shah S, Stapleton M, Wan KH, Yu C, Parsa B, Carlson JW, Chen X, Kapadia B, VijayRaghavan K, Gygi SP, Celniker SE, Obar RA, and Artavanis-Tsakonas S. A protein complex network of Drosophila melanogaster. Cell. 2011 Oct 28;147(3):690-703. DOI:10.1016/j.cell.2011.08.047 |
19. Bucko-Justyna M, Lipinski L, Burgering BM, and Trzeciak L. Characterization of testis-specific serine-threonine kinase 3 and its activation by phosphoinositide-dependent kinase-1-dependent signalling. FEBS J. 2005 Dec;272(24):6310-23. DOI:10.1111/j.1742-4658.2005.05018.x |
20. Jha KN, Wong L, Zerfas PM, De Silva RS, Fan YX, Spiridonov NA, and Johnson GR. Identification of a novel HSP70-binding cochaperone critical to HSP90-mediated activation of small serine/threonine kinase. J Biol Chem. 2010 Nov 5;285(45):35180-7. DOI:10.1074/jbc.M110.134767 |
21. Sosnik J, Miranda PV, Spiridonov NA, Yoon SY, Fissore RA, Johnson GR, and Visconti PE. Tssk6 is required for Izumo relocalization and gamete fusion in the mouse. J Cell Sci. 2009 Aug 1;122(Pt 15):2741-9. DOI:10.1242/jcs.047225 |

Omitted References

1. Andrews pmid=11116097
2. Barrios-Rodiles pmid=15761153
3. Borghese pmid=16580994