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 and tumour cell growth and metastasis.

Selected Research Publications

Steinberg F, Gallon M, Winfield M, Thomas E, Bell AJ, Heesom KJ, Tavaré JM, Cullen PJ: A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport. Nature Cell Biology 15, 461-471 (2013). [News and Views. Pfeffer SR: A nexus for receptor recycling. Nature Cell Biology 15, 446-448]. [F1000 - confirmation, interesting hypothesis, new finding].

van Weering JRT, Sessions RB, Traer CJ, Kloer DP, Bhatia VK, Stamou D, Carlsson SR, Hurley JH, Cullen PJ: Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules. EMBO Journal 31, 4466-4480 (2012). [F1000 - controversial new finding].

Steinberg F, Heesom KJ, Bass MD, Cullen PJ: Sorting nexin-17 protects integrins from degradation by sorting between lysosomal and recycling pathways. Journal of Cell Biology 197, 219-230 (2012). [In this Issue. Leslie M: Wait, save that integrin! Journal of Cell Biology 197, 162 (2012)]. [Dispatch. Calderwood DA, Brahme NN: Cell adhesion: A FERM grasp of the tail sorts out integrins. Current Biology 22, R692-R694 (2012)]. [F1000 - recommended].

Cullen PJ, Korswagen HC: Sorting nexins provide diversity for retromer-dependent trafficking events. Nature Cell Biology 14, 29-37 (2012).

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*: A sorting nexin-3 dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature Cell Biology 13, 914-923 (2011). ‡joint 2nd authors. *joint senior/corresponding authors. [News and Views. Johannes L, Wunder C: The SNXy flavours of endosomal sorting. Nature Cell Biology 13, 884-886 (2011)]. [Have you seen? Spang A: Signalling gets sorted by retromer. EMBO Journal 30, 2988-2989 (2011)]. [F1000 – must read].

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

Cullen PJ: Endosomal sorting and signalling: an emerging role for sorting nexins. Nature Reviews: Molecular Cell Biology 9, 574-582 (2008).

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

Rutherford AC, Traer CJ, Wassmer T, Pattni K, Bujny MV, Carlton JG, Stenmark H, Cullen PJ: The mammalian phosphatidylinositol 3 monophosphate 5-kinase PIKfyve regulates endosome-to-TGN retrograde transport. J Cell Sci 119, 3944-3957 (2006).

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

Other Selected Research Publications From Our Studies Of Phosphoinositide And Small GTPase Signaling

Jin H, Wang X, Ying J, Wong AHY, Cui Y, Srivastava G, Shen Z, Li E-M, Zhang Q, Jin J, Kupzig S, Chan ATC, Cullen PJ*, Tao Q*: Epigenetic silencing of a Ca2+-regulated Ras GAP RASAL, defines a new mechanism of Ras activation in human cancers. Proceedings National Academy Sciences USA 104, 12353-12358 (2007). *Joint senior/corresponding authors.

Kupzig S, Walker SA, Cullen PJ: The frequencies of Ca2+ oscillations are optimized for efficient Ca2+-mediated activation of Ras and the ERK/MAPK cascade. Proceedings National Academy Sciences USA 102, 7577-7582 (2005).

Walker SA, Kupzig S, Bouyoucef D, Davies LC, Tsuboi, T., Bivona TG, Cozier GE, Lockyer PJ, Buckler A, Rutter GA, Allen MJ, Philips MR, Cullen PJ: Identification of a Ras GTPase-activating protein regulated by receptor-mediated Ca2+ oscillations. EMBO Journal 23, 1749-1760 (2004).

Bivona TG, de Castro IG, Ahearn IM, Grana TM, Chiu VK, Lockyer PJ, Cullen PJ, Pellicer A, Cox AD, Philips MR: Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694-698 (2003). [News and Views. Di Fiore PP: Signal Transduction: life on Mars, cellularly speaking. Nature 424, 624-625 (2003)].

Lockyer PJ, Kupzig S, Cullen PJ: CAPRI regulates Ca2+-dependent inactivation of the Ras-MAP kinase pathway. Current Biology 11, 51-56 (2001). [Editor’s Choice: Calcium signals stop through CAPRI. Science STKE Issue 89, p.tw6 (2001)].

Lockyer PJ, Wennström S, Kupzig S, Venkateswarlu K, Downward J, Cullen PJ. Identification of the Ras GTPase-activating protein GAP1m as a phosphatidylinositol-3,4,5-trisphosphate-binding protein in vivo. Current Biology 9, 265-268 (1999).

Venkateswarlu K, Oatey PB, Tavaré JM, Cullen PJ: Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires PI 3-kinase. Current Biology 8, 463-466 (1998). [Dispatch. Irvine RF: Inositol phospholipids: Translocation, translocation, translocation….. Current Biology 8, R557-559 (1998)].

Lockyer PJ, Bottomley JR, Reynolds JS, McNulty TJ, Venkateswarlu K, Potter BV, Dempsey CE, Cullen PJ. Distinct subcellular localisations of the putative inositol 1,3,4,5-tetrakisphosphate receptors GAP1IP4BP and GAP1m result from the GAP1IP4BP PH domain directing plasma membrane targeting.Current Biology 7, 1007-1010 (1997).

Cullen PJ, Hsuan JJ, Truong O, Letcher AJ, Jackson TR, Dawson AP, Irvine RF: Identification of a specific IP4-binding protein as a member of the GAP1 family. Nature 376, 527-530 (1995).

Thastrup O, Cullen PJ, Drøbak BK, Hanley MR, Dawson AP: Thapsigargin has a novel mechanism of action among tumour promoters: discharge of intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proceedings National Academy Sciences USA 87, 2466-2470 (1990).