The biology of thrombospondins and other modulatory extracellular matrix proteins
N. Anilkumar and Soren Prag
The second international meeting on the Biology of Thrombospondins and other Modulatory Extracellular
Matrix Proteins was held at the University of Wisconsin in Madison, between
June 4-8 this year. Madison is located at an isthmus between the two lakes,
Monona and Mendota, and the conference was held in the old buildings of
the University with a beautiful overview of the lake. The meeting was
perfectly organised by Deane Mosher with help from Josephine Adams. We
apologise that for reasons of space we cannot mention all the presentations
made at the meeting and have therefore chosen to highlight the main areas
of current activity and the new themes which emerged at the meeting.
Modulatory extracellular
matrix proteins are defined as non-constitutive matrix components which
act to regulate cell shape and behaviour. The major matrix protein families
in this grouping are the thrombospondins, the tenascins and SPARC (secreted
protein, acidic and rich in cysteine) family proteins. The meeting brought
together an inclusive international program of the major active labs to
cover current topics relating to the structures and functions of modulatory
matrix proteins.
Regulation
of Angiogenesis
The regulation
of angiogenesis is now a major focus for the development of therapeutics
to inhibit tumour growth. Thrombospondins-1 and -2 act to inhibit angiogenesis
in culture and in mice through interactions of the three thrombospondin
type 1 repeats (TSRs). The effects of thrombospondins-1 and -2 in inhibiting
angiogenesis, and their cellular mechanisms of action, was one of the
major important themes of this meeting. A pioneer in the field of thrombospondin
is Jack Lawler (Harvard, USA). At the meeting he described experiments
to characterise which portions of the TSRs are responsible for the
inhibition of tumour growth. Injection of recombinant protein, containing
different combinations of the repeats, into mice inhibited tumour growth
in a dose-dependent manner. The inhibition of tumour cell growth and induction
of apoptosis by the second TSR was dependent on inclusion of the transforming
growth factor-b (TGF-b)
activating sequence.
Olga Volpert (Northwestern University, USA) described the signalling pathway responsible
for these properties of thrombospondin-1. She presented how thrombospondin-1
activates the CD36 receptor at the surface of endothelial cells and initiates
a signalling cascade involving p53fyn, caspase-3 and the stress-activated
kinase p38 MAPK which leads to activation of a second caspase cascade.
This was impressively and convincingly shown using endothelial cells from
the respective null mice. The induction of endothelial cell apoptosis
by TSP-1 was inhibited upon addition of caspase inhibitors. Thus, the
fate of endothelial cells is likely determined by the equilibrium of survival
and apoptotic signalling cascades.
 Donald
Senger (Harvard, USA) talked about the role of collagen receptors
a1b1 and a2b1 in vascular endothelial growth factor (VEGF) driven angiogenesis.
VEGF induces a 5-7-fold increase in protein expression of these collagen
receptors on dermal microvascular endothelial cells, through induction
of the transcription of their mRNAs. VEGF did not induce increased expression
of other collagen-binding integrins. Induction of a1b1 and a2b1 expression
by VEGF promoted cell spreading on collagen I gels which was abolished
by a combination of a1-blocking and a2-blocking Abs. Strikingly, in vivo,
a combination of a1-blocking and a2-blocking Abs markedly inhibited VEGF-driven
angiogenesis.
Roy Silverstein (Cornell, USA) presented a detailed description of CD36 as the anti-angiogenic
receptor for thrombospondin-1. CD36-null mice show abnormal plasma lipid
and lipoprotein profiles and have marked impairment of fatty acid utilization
in several tissues. This is in agreement with the reported fatty acid
transport function of CD36. Although superficially normal, the CD36-null
mice have higher brain capillary densities that wild type controls and
fail to show any anti-angiogenic responses to TSP-1.
Joanne E. Murphy-Ullrich (University of Alabama, USA) discovered some years ago that thrombospondin-1
activates latent TGF-b by an inter-molecular inter-action involving the
peptide motif RFK between the first and second TSR. To determine the biological
significance of this effect, she showed that the phenotype of thrombospondin-1
null mice reverted towards the wild type when the null mice were treated
with peptides derived from the TSR. Moreover, treating wild-type animals
with blocking peptides derived from thrombospondin-1 could induce a phenotype
similar to that of TGF-b null animals.
Page 1 - Page 2 |
Home
BSCB Newsletter
Winter 2000
Contents
Editorial
News
BSCB Hooke Medal Winner
Committee changes
Web news
UKLSC Database
Cool pics wanted
Awards
Schools News
Features
Where next, GMOs?
Cell Biology in Europe - Portugal
Meeting Reports
BSCB Autumn Meeting Report
Thrombospondin Meeting |
| 
| 
| 
| 
BSCB Organization 
