Professor Pete Cullen
Professor Pete Cullen
University Walk, Clifton
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Endosomal sorting and signaling
The endosomal system comprises a series of functionally and morphologically heterogenous membrane compartments that are dynamically interconnected and function in the sorting and dispatching of cargo to specific cellular destinations. Following internalisation, receptors like those for the cation-independent mannose 6-phosphate (CI-MPR), transferrin (TfnR) and epidermal growth factor (EGFR) enter the early endosome from where a series of sorting events segregate them into separate trafficking iteniaries. The TfnR is recycled back to the plasma membrane either through a fast recycling route or, more slowly, via the juxtanuclear endocytic recycling compartment (ERC). In contrast, the EGFR is retained within the limiting membrane of the early endosome through recognition of a ubiquitin tag. This results in the ESCRT-mediated sorting of the receptor into intraluminal vesicles of the early endosome. These mature into late endosomes/multivesicular bodies (MVBs) that become competent to fuse with lysosomes, leading to EGFR degradation. Finally, the CI-MPR is sorted for retrieval back to the trans-Golgi network (TGN) through both early and late endosomal pathways.
Tubular and vesicular compleities of the endosomal network
A more complexed model of cargo sorting within the early endocytic network is emerging. Associated with the vacuolar region of the early endosome is a network of tubular profiles that have been variously refered to as the tubular sorting endosome (TSE)’ or ‘tubular endosomal network (TEN)’. These, and related tubular profiles like the “endosome-to-TGN transport carrier” (ETC), function as endosomal subdomains into which proteins are sorted for transport to specific cellular destinations. Carriers subsequently leave these subdomains transporting their cargo to specific cellular destinations. We know very little about how such tubular subdomains are formed or the functional components that define their architecture. Moreover, we do not understand how sorting is coupled with the formation and dynamics of these tubular ultra-structures. That said, one family of proteins increasingly being linked with these fundamental events are the sorting nexins.
Mammalian sorting nexins
Sorting nexins (SNXs) are a family of proteins classified by the presence of a particular type of phox-homology (PX) domain – the SNX-PX domain. These proteins have been identified across phyla, from yeast through to mammals - currently 10 yeast and 33 mammalian sorting nexins have been annotated. As PX domains function, in the most part, by binding phosphatidylinositol 3-monophosphate (PtdIns(3)P), sorting nexins are associated with PtdIns(3)P-enriched elements of the early endocytic network. From here they play diverse roles in endocytosis, endosomal sorting and endosomal signalling. For mammalian sorting nexins, three distinct sub-families have been described: SNX-BAR proteins (besides the SNX-PX domain these proteins also contain a C-terminal BAR domain), SNX-PX proteins (these appear to solely contain the SNX-PX domain) and the SNX-other proteins (in addition to the SNX-PX domain these proteins containing other motifs many of which appear to play a role in signalling). It should be stressed that because sorting nexin proteins are group through the presence of a SNX-PX domain it does not necessarily follow that all proteins will be involved in sorting events. Indeed, some sorting nexins appear to be involved in endosomal signalling.
Endocytic network, endosomal function
We are aiming to answer the following fundamental questions:
- Do different SNX-BAR proteins define distinct tubular elements of the tubulovesicular early endosome?
- Do SNX-BAR proteins couple membrane tubulation with the formation of sorting complex in order to drive cargo sorting?
- Is an ability of SNX-BAR proteins to associate with molecular motors important in longitudinal force generation during membrane fission, and long-range carrier transport between donor and recipient membranes?
- Do SNX-PX proteins act as cargo adaptors that allow cargo to “piggy back” onto pre-existing SNX-BAR driven transport pathways?
- Do sorting nexins co-ordinate endosomal sorting of internalised receptors with an ability to modulate receptor signalling?
Diseases related to this field of research
cancer, neurodegeneration, pathogenic infection
Processes and functions relevant to this work
Endosomal sorting and signaling, protein complex formation
Christopher Danson, Jacqueline Oakley, Colin Traer, Jan van Weering
Techniques in routine use
live and fixed cell confocal imaging, immuno-EM, 3D electron tomography, CLEM
- Hunt, SD, Townley, AK, Danson, CM, Cullen, PJ & Stephens, DJ 2013, Microtubule motors mediate endosomal sorting by maintaining functional domain organization. Journal of cell science.
- McGough, IJ & Cullen, PJ 2013, Clathrin is not required for SNX-BAR-retromer mediated carrier formation. Journal of cell science.
- Steinberg, F, Gallon, MJ, Winfield, MO, Thomas, EC, Bell, AJ, Heesom, KJ, Tavare, JM & Cullen, PJ 2013, A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport.. Nature Cell Biology.
- Weering, Jv, Verkade, P & Cullen, P 2012, SNX-BAR-mediated endosome tabulation is coordinated with endosome maturation. Traffic, vol 13(1)., pp. 94 - 107
- Steinberg, F, Heesom, K, Bass, M & Cullen, P 2012, SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. The Journal of Cell Biology, vol 197(2)., pp. 219 - 230
- Eva, R, Bouyoucef-cherchalli, D, Patel, K, Cullen, P & Banting, G 2012, IP3 3-kinase opposes NGF driven neurite outgrowth. PLoS One, vol 7(2)., pp. e32386 - e32386
- Weering, JRTv, 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 Journal, vol 31., pp. 4466-4480
- Cullen, P & Korswagen, H 2012, Sorting nexins provide diversity for retromer-dependent trafficking events. Nature Cell Biology, vol 14(1)., pp. 29 - 37
- Cullen, P & Carlton, J 2012, Phosphoinositides in Mammalian Endo-Iysosomal Network. in: T Balla, JD York, M Wymann (eds) Phosphoinositides II: The Diverse Biological Functions: Subcellular Biochemistry. Springer Dordrecht Heidelberg London New York, pp. 65 - 110
- Harterink, M, Port, F, Lorenowicz, M, McGough, I, Silhankova, M, Betist, M, Weering, Jv, Heesbeen, Rv, Middlekoop, T, Basler, K, Cullen, P & Korswagen, H 2011, A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature Cell Biology, vol 13 (8)., pp. 914 - 923
Full publications list in the University of Bristol publications system