Ossipova Olga, Bardeesy Nabeel, DePinho Ronald A, Green Jeremy B A
Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Nat Cell Biol. 2003 Oct;5(10):889-94. doi: 10.1038/ncb1048. Epub 2003 Sep 14.
Germline LKB1/STK11 mutations are associated with the cancer-prone Peutz-Jeghers syndrome (PJS) in humans, and nullizygosity provokes a poorly understood constellation of developmental perturbations in the mid-gestational mouse. To gain a better understanding of the processes regulated by LKB1, we have exploited the experimental merits of the developing Xenopus embryo. Here, specific inhibition of XEEK1, the Xenopus orthologue of LKB1, engendered developmental anomalies - shortened body axis and defective dorsoanterior patterning - associated previously with aberrant Wnt signalling. In line with this, LKB1/XEEK1 cooperates with the Wnt-beta-catenin signalling in axis induction and modulates the expression of Wnt-responsive genes in both Xenopus embryos and mammalian cells. We establish that LKB1/XEEK1 acts upstream of beta-catenin in the Wnt-beta-catenin pathway in vivo. LKB1/XEEK1 regulates glycogen synthase kinase (GSK)3beta phosphorylation and it is physically associated in vivo with GSK3beta and protein kinase C (PKC)-zeta, a known GSK3 kinase. These studies show that LKB1/XEEK1 is required for Wnt-beta-catenin signalling in frogs and mammals and provides novel insights into its role in vertebrate developmental patterning and carcinogenesis.
种系LKB1/STK11突变与人类易患癌症的黑斑息肉综合征（PJS）相关，而纯合缺失会在妊娠中期小鼠中引发一系列尚不清楚的发育紊乱。为了更好地理解LKB1所调控的过程，我们利用了非洲爪蟾胚胎发育的实验优势。在此，特异性抑制LKB1在非洲爪蟾中的同源物XEEK1会引发发育异常——体轴缩短和背前部模式缺陷——这些异常先前与异常的Wnt信号传导有关。与此一致的是，LKB1/XEEK1在轴诱导过程中与Wnt-β-连环蛋白信号传导协同作用，并调节非洲爪蟾胚胎和哺乳动物细胞中Wnt反应性基因的表达。我们证实，在体内，LKB1/XEEK1在Wnt-β-连环蛋白途径中作用于β-连环蛋白的上游。LKB1/XEEK1调节糖原合酶激酶（GSK）3β的磷酸化，并且在体内与GSK3β和蛋白激酶C（PKC）-ζ（一种已知的GSK3激酶）存在物理关联。这些研究表明，LKB1/XEEK1是青蛙和哺乳动物中Wnt-β-连环蛋白信号传导所必需的，并为其在脊椎动物发育模式形成和致癌作用中的作用提供了新的见解。
