A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis

Mhairi C. Towler, Sarah Fogarty, Simon A. Hawley, David A. Pan, David M. A. Martin, Nicolas A. Morrice, Afshan McCarthy, Maria N. Galardo, Silvina B. Meroni, Selva B. Cigorraga, Alan Ashworth, Kei Sakamoto, D. Grahame Hardie (Lead / Corresponding author)

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    Abstract

    LKB1 was discovered as a tumour suppressor mutated in Peutz-Jeghers syndrome, and is a gene involved in cell polarity as well as an upstream protein kinase for members of the AMP-activated protein kinase family. We report that mammals express two splice variants caused by alternate usage of 3'-exons. LKB1(L) is the previously described form, while LKB1(S) is a novel form in which the last 63 residues are replaced by a unique 39-residue sequence lacking known phosphorylation (Ser(431)) and farnesylation (Cys(433)) sites. Both isoforms are widely expressed in rodent and human tissues, although LKB1(S) is particularly abundant in haploid spermatids in the testis. Male mice in which expression of Lkb1(S) is knocked out are sterile, with the number of mature spermatozoa in the epididymis being dramatically reduced, and those spermatozoa that are produced have heads with an abnormal morphology and are non-motile. These results identify a previously undetected variant of LKB1, and suggest that it has a crucial role in spermiogenesis and male fertility.

    Original languageEnglish
    Pages (from-to)1-14
    Number of pages14
    JournalBiochemical Journal
    Volume416
    Issue number1
    DOIs
    Publication statusPublished - 15 Nov 2008

    Keywords

    • AMP-activated protein kinase (AMPK)
    • LKB1
    • male fertility
    • spermiogenesis
    • splice variants
    • ACTIVATED PROTEIN-KINASE
    • SERINE-THREONINE KINASE
    • METABOLIC CHECKPOINT
    • CELLULAR-ENERGY
    • PHOSPHORYLATION
    • SUBSTRATE
    • CELLS
    • MUTATIONS
    • PATHWAY
    • STRAD

    Cite this

    Towler, M. C., Fogarty, S., Hawley, S. A., Pan, D. A., Martin, D. M. A., Morrice, N. A., McCarthy, A., Galardo, M. N., Meroni, S. B., Cigorraga, S. B., Ashworth, A., Sakamoto, K., & Hardie, D. G. (2008). A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis. Biochemical Journal, 416(1), 1-14. https://doi.org/10.1042/BJ20081447