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

TY - JOUR

T1 - A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis

AU - Towler, Mhairi C.

AU - Fogarty, Sarah

AU - Hawley, Simon A.

AU - Pan, David A.

AU - Martin, David M. A.

AU - Morrice, Nicolas A.

AU - McCarthy, Afshan

AU - Galardo, Maria N.

AU - Meroni, Silvina B.

AU - Cigorraga, Selva B.

AU - Ashworth, Alan

AU - Sakamoto, Kei

AU - Hardie, D. Grahame

PY - 2008/11/15

Y1 - 2008/11/15

N2 - 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.

AB - 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.

KW - AMP-activated protein kinase (AMPK)

KW - LKB1

KW - male fertility

KW - spermiogenesis

KW - splice variants

KW - ACTIVATED PROTEIN-KINASE

KW - SERINE-THREONINE KINASE

KW - METABOLIC CHECKPOINT

KW - CELLULAR-ENERGY

KW - PHOSPHORYLATION

KW - SUBSTRATE

KW - CELLS

KW - MUTATIONS

KW - PATHWAY

KW - STRAD

UR - https://www.scopus.com/pages/publications/56049117647

U2 - 10.1042/BJ20081447

DO - 10.1042/BJ20081447

M3 - Article

C2 - 18774945

SN - 0264-6021

VL - 416

SP - 1

EP - 14

JO - Biochemical Journal

JF - Biochemical Journal

IS - 1

ER -