A moving account of degradation: receptor signalling, endosomes and motor proteins

内体是调节多种信号通路的枢纽，因为内体分选决定细胞表面信号受体的命运。激活的受体被内化到内体中。一些从内体返回到表面并继续发出信号，一些在“信号内体”内保持活性，而另一些则被分选为溶酶体降解。这种选择对于确定受体信号传导对细胞命运的影响至关重要。表皮生长因子受体（EGFR）用作信号传导受体的示例性模型，其运输与信号传导输出相关。EGFR是否保持活性或降解的决定是由几个膜运输开关决定的，但也是在高度运动的背景下设定的：货物向溶酶体的进展伴随着内体从外周向细胞中心的向内运动，同时再循环途径也受到空间控制。总之，这创造了一种时空信号模式，有助于控制细胞命运。虽然内体运动在短范围内由肌动蛋白控制，但基于微管的运动对于在细胞外周和细胞中心之间移动内体是至关重要的，并且需要负端微管运动蛋白动力蛋白。该项目旨在确定EGFR依赖性信号传导，特别是MAP激酶家族信号传导，如何控制内体（包括含有EGFR的内体）的动力蛋白依赖性运动。博士项目的总体目标是确定内吞膜运输步骤如何与内体运动协调，以及这种耦合如何与EGFR依赖性信号传导相关联。

Endosomes are hubs for regulating multiple signaling pathways, because endosomal sorting determines the fate of cell surface signalling receptors. Activated receptors are internalised into endosomes. Some return to the surface from the endosome and continue to signal, some remain active within a 'signalling endosome', whilst others are sorted towards lysosomal degradation. This choice is crucial for determining the impact of receptor signalling on cell fate. Epidermal growth factor receptor (EGFR) serves as an exemplary model of a signaling receptor whose trafficking is linked to the signaling output. The decision of whether EGFR remains active or is degraded is determined by several membrane trafficking switches, but also is set against a highly motile backdrop: progression of cargo towards the lysosome is accompanied by the inward movement of endosomes from the periphery towards the cell centre, whilst recycling pathways are also spatially controlled. In all, this creates a spatiotemporal pattern of signaling that is instrumental in controlling cell fate. Whilst endosome motility is governed over short ranges by actin, microtubule-based movement is critical for moving endosomes between the cell periphery and cell centre, and requires the minus-end microtubule motor protein dynein. This project seeks to establish how EGFR-dependent signalling, and specifically MAP kinase family signaling, controls dynein-dependent motility of endosomes, including those containing EGFR. The overall objective of the PhD project is to identify how endocytic membrane trafficking steps are coordinated with endosome motility, and how such coupling is linked to EGFR-dependent signalling.