Functional Crosstalk of the Pseudophosphatase STYX with F-box proteins

假磷酸酶在生物学和疾病中的作用仍然知之甚少。我们最近发现假磷酸酶STYX通过丝裂原活化蛋白激酶调节信号传导。然而，由于STYX是无催化活性的，我们假设这种假磷酸酶可能已经进化到调节激酶以外的其他家族蛋白。通过绘制STYX的相互作用组，我们发现它与几种属于泛素转移蛋白的Cullin-RING连接酶的F-box蛋白（FBPs）相互作用，这些蛋白调节哺乳动物蛋白质组的五分之一的营业额。其中一种FBPs是一种名为FBXW 7的蛋白质，这是一种众所周知的肿瘤抑制蛋白，在9%的人类癌症中发生突变。我们的目标是：（一） 表征STYX和FBPs的二元相互作用相对于它们的相互作用中涉及的结构域。（二） 调查STYX是否是任何FBPs的底物（iii） 探索STYX-FBXW 7在癌症背景下的联系。除了STYX和FBXW 7对增殖和凋亡的影响的细胞测定外，我们还将分析大量患者以确定STYX/FBXW 7差异表达对乳腺癌患者预后的影响。总的来说，我们的研究将导致更好地了解假磷酸酶STYX在细胞生物学中的作用。此外，我们从癌症患者中获得的结果可能会导致STYX作为新的治疗靶点或作为预后标志物的建立。

Pseudophosphatase remain poorly understood with respect to their roles in biology and disease. We recently showed that the pseudophosphatase STYX regulates signaling by mitogen activated protein kinases. However, since STYX is catalytically inactive we hypothesized that this pseudophosphatase might have evolved to regulate other family proteins beyond kinases. By mapping the interactome of STYX we found that it interacts with several F-box proteins (FBPs) that belong to the Cullin-RING ligases of ubiquitin transfer proteins that regulate the turnover of a fifth of the mammalian proteome. One of the FBPs is a protein called FBXW7, a well-known tumor-suppressor protein mutated in 9% of all human cancers. Our goals are:(i) characterization the binary interaction of STYX and FBPs with respect to the domains involved in their interaction. (ii) Investigate whether STYX is a substrate for any of the FBPs(iii) Explore the STYX-FBXW7 connection in the context of cancer. Beside cellular assays for effects of STYX and FBXW7 on proliferation and apoptosis, we will analyze a large cohort of patients to determine effects of differential STYX/FBXW7 expressions of prognosis of breast cancer patients. Overall, our study will lead to a better understanding of the role of the pseudophosphatase STYX in cell biology. Moreover, our results from cancer patients could lead to the establishment of STYX as a new therapeutic target or as a prognostic marker.