A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis.
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.
Towler
Mhairi C
MC
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
Fogarty
Sarah
S
Hawley
Simon A
SA
Pan
David A
DA
Martin
David M A
DM
Morrice
Nicolas A
NA
McCarthy
Afshan
A
Galardo
María N
MN
Meroni
Silvina B
SB
Cigorraga
Selva B
SB
Ashworth
Alan
A
Sakamoto
Kei
K
Hardie
D Grahame
DG
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007248:Infertility, Male / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016415:Sequence Alignment; D013087:Spermatids / Q000201:enzymology; D013091:Spermatogenesis / Q000502:physiology*; D013737:Testis / Q000648:ultrastructure
D007527:Isoenzymes; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases