Daniel Cutler Research Group

1979 - BSc University of Leicester.
1982 - PhD University of Warwick.
Daniel Cutler
Tel: 020 7679 7808
Fax: 020 7679 7805
Awards: 
1982 - EMBO Fellow
1985 - NATO Fellow
Previous Posts: 
1986 - Department of Biochemistry, Imperial College.
1991 - MRC Laboratory for Cell Biology, Cell Biology Unit, and Department of Biochemistry and Molecular Biology, UCL

Endothelial Cell Biology: Membrane traffic, Inflammation and Haemostasis

Endothelial cells
contain a storage organelle, Weibel-Palade Bodies (WPB), which contains key
components of both inflammatory and haemostatic processes. As a rapid-response
system, the WPB are of critical importance in initiating haemostatic and
inflammatory responses within the rapidly-changing vascular environment.

For example, the
leukocyte receptor P-selectin is found within the WPB membrane. A key event in
the initiation of inflammation is the appearance of P-selectin on the apical
surface of endothelial cells by exocytosis of WPB. Once exposed to the blood
via exocytosis of the WPB, P-selectin initiates leukocyte recruitment by
binding P-selectin glycoprotein ligand (PSGL)-1 on the leukocyte surface. We
recently discovered that CD63, of previously unknown function, clusters the
P-selectin into macromolecular assemblies that are essential to its function.
This initial recruitment leukocytes leads to rolling which eventually
progresses to their passage across the endothelial barrier into the damaged
tissue.

The major content
protein of WPB is von Willebrands factor (VWF), an adhesive glycoprotein that
plays a major role in primary haemostasis. This very large highly multimerised
protein is stored within the WPB coiled up as proteinacious tubules Mutations
within VWF are the commonest cause of the inherited bleeding disorder Von
Willebrands Disease. In addition to mutations causing a loss of platelet
binding or other direct haemostatic problems, mutations in VWF can affect the
formation of the protein tubules, leading to formation of damaged, poorly
functional WPB.

Recent advances in
microscopy and in bioinformatics allowed us to measure the length of millions
of WPB. This revealed that their size increases in half-micron steps. These in
turn arise from the assembly of the WPB from 500nm subunits. We discovered that
the subunits are brought together in the trans-Golgi where they assemble into
the wide distribution of lengths that we find in human cells. Finally, we can
then manipulate the length of WPB and show that short WPB are much less
efficient at supporting platelet recruitment, and thus initiating primary
haemostasis. 

Organelle sizing by Golgi architecture: Weibel-Palade bodies (in
green) are cigar-shaped endothelial specific secretory granules with a central
role in hemostasis and inflammation.The architectural status of the Golgi
apparatus (red, GM130, and blue, TGN46) determines the size of the WPBs
produced. The vertebrate ribbon format permits the generation of large WPBs
(center of the figure); its unlinking into separate units, the ministacks
(disposed in a circle), results in small organelles being made.

Lab Members: 
Francesco Ferraro
Kimberley Harrison-Lavoie
Mafalda Lopes da Silva
Jessica McCormack
Publications

Number of publications: 66.

2014

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