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Endosomal sorting and signalling

The endosomal network comprises a series of interconnected membrane bound compartments that in regulating the sorting and signalling of proteinaceous cargoes including receptors, transporters and adhesion molecules, orchestrates and fine-tunes numerous cellular processes. A major challenge is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the pathoetiology of human disease.

To achieve such an understanding we believe that one must take a global, integrated view, not only in individual cells but also within the physiological complexities of developing organisms. In combining molecular studies, including the power of quantitative proteomics, with genetic studies in model organisms our research aims to define the underlying defects in endosomal sorting and signalling that occur in various diseases, in particular Alzheimer's and Parkinson's diseases.

Selected Research Publications

  • McMillan KJ, Gallon M, Jellett AP, Clairfeuille T, Tilley FC, McGough IJ, Danson CM, Heesom KJ, Wilkinson KA, Collins BM, Cullen PJ. (2016). Atypical Parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins. J Cell Biol in press.

  • Gallon M, Clairfeuille T, Steinberg F, Mas C, Ghai R, Sessions RB, Teasdale RD, Collins BM, Cullen PJ. (2014). A unique PDZ domain and arrestin-like fold interaction reveals mechanistic details of endocytic recycling by SNX27-retromer. Proc Natl Acad Sci USA 111, E3604-3613.

  • McGough IJ, Steinberg F, Jia D, Barbuti PA, McMillan KJ, Heesom KJ, Caldwell MA, Billadeau DD, Rosen MK, Cullen PJ. (2014). Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr Biol 24, 1670-1676.

  • Steinberg F, Gallon M, Winfield M, Thomas E, Bell AJ, Heesom KJ, Tavaré JM, Cullen PJ. (2013). A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport. Nat Cell Biol 15, 461-471. [N&V. Pfeffer SR: A nexus for receptor recycling. Nat Cell Biol 15, 446-448].

  • van Weering JRT, Sessions RB, Traer CJ, Kloer DP, Bhatia VK, Stamou D, Carlsson SR, Hurley JH, Cullen PJ. (2012). Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules. EMBO J 31, 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. J Cell Biol 197, 219-230. [In this Issue. Leslie M: Wait, save that integrin! J Cell Biol 197, 162 ]. [Dispatch. Calderwood DA, Brahme NN: Cell adhesion: A FERM grasp of the tail sorts out integrins. Curr Biol 22, R692-R694].

  • Harterink M, Port F‡, Lorenowicz MJ‡, McGough IJ‡, Sikankova M, Betist MC, van Weering JRT, van Heesbeen RGHP, Middelkoop T, Basler K, Cullen PJ*, Korswagen HC*. (2011). A sorting nexin-3 dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nat Cell Biol 13, 914-923. ‡joint 2nd authors. *joint senior/corresponding authors. [N&V. Johannes L, Wunder C:The SNXy flavours of endosomal sorting. Nat Cell Biol 13, 884-886]. [Have you seen? Spang A: Signalling gets sorted by retromer. EMBO J 30, 2988-2989].

  • Wassmer T, Attar N, Harterink M, van Weering JRT, Traer CJ, Oakley J, Goud B, Stephens DJ, Verkade P, Korswagen HC, Cullen PJ. (2009). The retromer coat complex coordinates endosomal sorting and dynein-mediated transport with carrier recognition by the trans-Golgi network. Dev Cell 17, 110-122.

  • Traer CJ, Rutherford AC, Palmer KJ, Wassmer T, Oakley JD, Carlton JG, Kremerskothen J, Stephens DJ, Cullen PJ. (2007). Sorting nexin-4 co-ordinates endosomal sorting of transferrin receptor with dynein-mediated transport into the endocytic recycling compartment. Nat Cell Biol 9, 1370-1380.

  • Carlton JG, Bujny MV, Peter BJ, Oorschot VMJ, Rutherford AC, Mellor H, Klumperman J, McMahon HT, Cullen PJ. (2004). Sorting nexin-1 mediates tubular endosome-to-TGN transport through co-incidence sensing of high curvature membranes and 3-phosphoinositides. Curr Biol 14, 1791-1800. [Research Roundup. LeBrasseur N: SNX1 hugs the curves. J Cell Biol 4, 581].

  • Selected Reviews

  • Cullen PJ, Korswagen HC. (2012). Sorting nexins provide diversity for retromer-dependent trafficking events. Nat Cell Biol 14, 29-37.

  • Cullen PJ. (2008). Endosomal sorting and signalling: an emerging role for sorting nexins. Nat Rev Mol Cell Biol 9, 574-582.