Tom Carter group
Secretory organelle formation, trafficking and exocytosis
To survive and function correctly cells must sense and respond to their environment. This is largely achieved through the incorporation of integral membrane proteins (e.g. hormone receptors, ion channels, adhesion molecules etc) and lipid components into the cell surface membrane and the secretion of soluble proteins in to the external environment (e.g. hormones, transmitters, morphogens etc). The correct delivery of virtually all such molecules to the cell surface or extracellular milieu involves a complex intracellular machine collectively called the secretory pathway.
Our group works on the secretory pathway using Endothelial Cells (ECs) and the Weibel-Palade body (Figure 1), as our model system. We use molecular, biochemical and live cell optical imaging techniques to study the formation, trafficking (Movie 1) and exocytosis (Movies 2-4) and physical properties (Movie 7) of secretory organelles; the containers that store and ultimately deliver proteins to the cell surface and extracellular milieu.
Figure 1 - Weibel Palade bodies
Click image to view at full-size
Immunofluorescence (confocal) image of a single human umbilical vien endothelial cell (HUVEC) triple stained for 3 separate WPB specific cargo molecules including VWF (green). N; cell nucleus. EM images show longitudinal (left) and cross sections (right) through WPBs in a plastic embedded HUVEC (EM images courtesy of Lindsay Hewlett and Matthew Hannah, NIMR).
- We collaborate with David Ogden (Universite Paris Descartes, France) and Gregor Zupancic (Univ. of Llubljana, Slovenia) to refine the analysis of high resolution optical approaches to study exocytosis of single secretory organelles, with Paul Skehel (Edingurgh Univ.), Matthew Hannah (NIMR) and Vincent O'Connor (Southampton Univ.) to investigate the molecular basis of exocytosis in endothelium, with Paul Skehel, Matthew Hannah and Paul le Tissier (NIMR) in the development of animal models in which to study exocytosis in vivo.
- We collaborate with Matthew Hannah and Peter Rosenthal (NIMR) on high resolution structural analysis, by cryo-EM tomography, of secretory granules, their cargo and exocytosis, and with Justin Molloy (NIMR) and Gregory Mashanov on the behaviour of secretory granule membrane proteins at the single molecule level within living endothelial cells.
- In conjunction with Matthew Hannah, David Ogden, Gregor Zupancic, Prof. Michelle Peckham (Leeds Univ.) and Justin Molloy we are working on the role of the cytoskeleton and associated molecular motors in secretory vesicle trafficking and exocytosis in endothelial cells.
- We collaborate with Prof. Caroline Wheeler-Jones (RVC, London) to study the molecular regulation of protease-activated receptor medaited induction of cyclooxygenase-2 prostacyclin release in endothelial cells.
- Kiskin, NI; Hellen, N; Babich, V; Hewlett, L; Knipe, L; Hannah, MJ and Carter, T (2010)
Protein mobilities and P-selectin storage in Weibel-Palade bodies.
Journal of Cell Science 123, 2964-2975 PubMed abstract
- Knipe, L; Meli, A; Hewlett, L; Bierings, R; Dempster, J; Skehel, P; Hannah, MJ and Carter, T (2010)
A revised model for the secretion of tPA and cytokines from cultured endothelial cells.
Blood Epub ahead of print, PubMed abstract
- Berriman JA, Li S, Hewlett LJ, Wasilewski S, Kiskin FN, Carter T, Hannah MJ, Rosenthal PB. (2009)
Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells.
Proceedings of the National Academy of Sciences of the United States of America 106, 17407-17412 PubMed abstract
- Babich V, Knipe L, Hewlett L, Meli A, Dempster J, Hannah MJ, Carter T. (2009)
Differential effect of extracellular acidosis on the release and dispersal of soluble and membrane proteins secreted from the Weibel-Palade body.
Journal of Biological Chemistry 284, 12459-12468 PubMed abstract
- Babich V, Meli A, Knipe L, Dempster JE, Skehel P, Hannah MJ, Carter T. (2008)
Selective release of molecules from Weibel-Palade bodies during a lingering kiss.
Blood 111, 5282-5290 PubMed abstract
- Erent, M; Meli, A; Moisoi, N; Babich, V; Hannah, MJ; Skehel, P; Knipe, L; Zupancic, G; Ogden, D and Carter, TD (2007)
Rate, extent and concentration-dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells.
Journal of Physiology 581, 195-212 PubMed abstract
Our research themes
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