LKB1 - linking the regulation of cell polarity to cell proliferation control in physiological state and cancer

细胞极性的建立和维持是多细胞生物最重要的问题之一。值得注意的是，许多调节细胞极性的关键因素也涉及细胞增殖和生长抑制的控制，这些在转化细胞中严重受损。肿瘤抑制因子LKB1已被证明参与两个过程-调节细胞极性和控制细胞增殖。尽管一些研究已经提供了LKB1发挥作用的几个过程的证据，但LKB1本身是如何被调节的仍不清楚。此外，哪些下游效应物对其控制细胞极性和细胞增殖起关键作用仍不清楚。由于LKB1作为一种“主激酶”能够激活几种下游激酶和途径，因此很难分析其在特定机制中的作用。因此，我们在模式生物黑腹果蝇中发现了LKB1的新的相互作用伙伴和底物。通过对LKB1底物及下游靶点磷酸化事件的分析，探讨LKB1在生理状态及肿瘤中的作用机制。因此，我们将首先使用果蝇神经干细胞和其他极化细胞作为模型系统。获得的结果随后将在脊椎动物系统中进行测试。

The establishment and maintenance of cell polarity is one of the most important issues in multicellular organisms. Notably, many key factors regulating cell polarity are also implicated in the control of cell proliferation and growth inhibition, which are strongly impaired in transformed cells. The tumour sup-pressor LKB1 has been shown to be involved in both processes – regulation of cell polarity and control of cell proliferation. Although some studies have already provided evidence about several processes in which LKB1 functions, it is still unclear how LKB1 itself is regulated. Further it still remains elusive which downstream effectors are crucial for its control of cell polarity and cell proliferation.Due to the fact that LKB1 as a “master kinase” is capable to activate several downstream kinases and pathways it is difficult to dissect its role in a distinct mechanism. Therefore we identified new interac-tion partners and substrates for LKB1 in the model organism Drosophila melanogaster. From the anal-ysis of the phosphorylation events of LKB1 substrates and downstream targets we aim to draw con-clusions about the mechanisms underlying LKB1 function in physiological state and cancer. Therefore we will initially use Drosophila neural stem cells and other polarized cells as model system. Obtained results will subsequently be tested in vertebrate systems.