Asymmetric protein sorting via localizd translation - The role of ZBP protein in directing mRNA localization and translation

通过RNA结合蛋白(RBPs)和microRNAs(MiRs)转录后调控基因的表达，可以在发育、分化以及肿瘤细胞中对蛋白质的表达进行时空微调。在发育中的神经元中经常观察到对mRNA翻译的空间控制，这需要将翻译沉默的mRNAs运输到突起中。人们认为这一过程是通过细胞质蛋白质-RNA复合体来促进的，通常被归类为mRNPs。IGF2BP(IGF2mRNAbindingProtein)蛋白家族是发育中神经元空间调控蛋白质合成的重要调节因子，又称ZBPs。在后者，成纤维细胞和肿瘤来源的细胞中，ZBP1控制着肌动蛋白(ACTB)的翻译和在某些情况下的运输。当Src介导ZBP1的酪氨酸磷酸化时，ACTB mRNA的翻译被激活。在神经元生长锥中，这种对ACTB蛋白合成的空间控制被认为是直接生长锥突起和引导的。随着这些项目的提出，我们打算表征含有ZBP1的mRNPs的组成和翻译后修饰，以破译它们在时空方式指导ACTB mRNA翻译中的作用。

Posttranscriptional control of gene expression by RNA-binding proteins (RBPs) and microRNAs (miRs) allows the spatiotemporal fine tuning of protein expression during development, differentiation but also in neoplastic cells. Spatial control of mRNA translation is frequently observed in developing neurons and requires the transport of translationally silenced mRNAs into neurites. It is assumed that this process is facilitated via cytoplasmic protein-RNA complexes, typically classified as mRNPs. Members of the RNA-binding IGF2BP (IGF2 mRNA binding protein) protein family, also termed ZBPs (Zipcode binding proteins), are essential regulators of spatially controlled protein synthesis in developing neurons. In the latter, fibroblasts but also tumor-derived cells, ZBP1 controls translation and in some cases transport of the ß-actin (ACTB) mRNA. Upon Src-mediated tyrosine phosphorylation of ZBP1, ACTB mRNA translation is activated. In neuronal growth cones this spatial control of ACTB protein synthesis is presumed to direct growth cone protrusion and guidance. With the projects proposed, we intend to characterize the composition and posttranslational modifications of ZBP1-containing mRNPs to decipher their role in directing ACTB mRNA translation in a spatiotemporal manner.