The endocytic network in health and disease.
The endosomal network comprises interconnected membranous compartments whose primary function is to receive and sort cargo from the plasma membrane and the biosynthetic pathway. In sorting an array of cargoes, including proteins, lipids, nutrients, solutes, etc, to a variety of cellular destinations, the network performs an essential, evolutionary conserved function in regulating and fine-tuning numerous processes within the cell. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the etiology and pathology of human disease.
To date our understanding of endosomal sorting has been restricted by a tendency to focus on individual ‘model’ cargos, and the ‘isolated’ characterization of protein complexes that define individual retrieval pathways. To achieve a thorough understanding we must break new ground and take a global view of cargo proteins and an integrated approach to how the mechanistic complexities of multiple retrieval complexes are orchestrated, not only in individual cells but within the complexities of a developing organism. In the laboratory we seek to address these issues by combining new experimental protocols utilizing the power of SILAC-based quantitative proteomics to achieve an unbiased global quantitative analysis of cargo retrieval, with a focused in vitro and in vivo analysis of the largest evolutionary conserved protein group involved with endosomal sorting, the sorting nexins. In defining the importance of endosomal sorting in the formation of morphogenic gradients, integrin turnover, nutrient sensing and uptake, and the regulation of planar cell polarity, we aim to generate an integrated view of the interface between endosomal sorting pathways and organism development and physiology.
Chris Danson, Dineke Folmer, Matthew Gallon, OJ Hemmings, Ian McGough, Florian Steinberg, Colin Traer and Jan van Weering.
McGough IJ, Cullen PJ. (2012) Clathrin is not required for SNX-BAR-retromer mediated carrier formation. Journal of Cell Science. In press.
van Weering JRT, Sessions RB, Traer CJ, Kloer DP, Bhatia VK, Stamou D, Carlsson SR, Hurley JH, Cullen PJ. (2012) In vitro SNX-BAR assembly reveals molecular details of distinct endosomal tubule formation. EMBO Journal. 31(23): 4466-4480.
Steinberg F, Heesom KJ, Bass MD, Cullen PJ. (2012) Sorting nexin-17 protects integrins from degradation by sorting between lysosomal and recycling pathways. Journal of Cell Biology. 197: 219-230. [see In This Issue. Mitch Leslie: Wait, save that integrin! Journal of Cell Biology 197, 152 (2012)]. [F1000 – recommended].
van Weering JR, Vekarde P, Cullen PJ. (2012) SNX-BAR-mediated endosome tubulation is co-ordinated with endosome maturation. Traffic. 13: 94-107. [F1000 – recommended].
Cullen PJ, Korswagen HC. (2012) Sorting nexins provide diversity for retromer-dependent trafficking events. Nature Cell Biology. 14: 29-37.
Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JRT, van Heesbeen RG, Middelkoop TC, Basler K, Cullen, PJ, Korswagen HC. (2011) A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature Cell Biology. 13: 914-923. [see News and Views. Johannes L, Wunder C. (2011) The SNXy flavours of endosomal sorting. Nature Cell Biology 13, 884-886. Have you seen? Spang A: Signalling gets sorted by retromer. EMBO Journal 30, 2988-2989 (2011)]. [F1000 – must read].