Towler Mhairi C, Fogarty Sarah, Hawley Simon A, Pan David A, Martin David M A, Morrice Nicolas A, McCarthy Afshan, Galardo María N, Meroni Silvina B, Cigorraga Selva B, Ashworth Alan, Sakamoto Kei, Hardie D Grahame
Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
Biochem J. 2008 Nov 15;416(1):1-14. doi: 10.1042/BJ20081447.
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.
LKB1最初是作为在黑斑息肉综合征中发生突变的肿瘤抑制因子被发现的，它是一个参与细胞极性的基因，也是AMP激活的蛋白激酶家族成员的上游蛋白激酶。我们报道，哺乳动物表达由3'-外显子交替使用导致的两种剪接变体。LKB1(L)是先前描述的形式，而LKB1(S)是一种新形式，其中最后63个残基被一个独特的39个残基序列取代，该序列缺乏已知的磷酸化（Ser(431)）和法尼基化（Cys(433)）位点。两种异构体在啮齿动物和人类组织中均广泛表达，尽管LKB1(S)在睾丸中的单倍体精子细胞中特别丰富。Lkb1(S)表达被敲除的雄性小鼠不育，附睾中成熟精子的数量显著减少，所产生的精子头部形态异常且无运动能力。这些结果鉴定出了一种先前未被检测到的LKB1变体，并表明它在精子发生和雄性生育中具有关键作用。
