Tumorigenesis: Route master

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Matrix metalloproteinase membrane type 1 (MT1-MMP) can modify signal transduction through platelet-derived growth factor B (PDGFB) and its receptor PDFGR beta to regulate development of micro-vasculature.

Matrix metalloproteinases (MMPs), which include membrane type 1 (MT1)-MMP, are mainly known for their hydrolysis of extracellular matrix (ECM) components. But recently it has become apparent that they have a much wider substrate repertoire. Stephen Weiss and colleagues show that MT1-MMP can modify signal transduction through platelet-derived growth factor B (PDGFB) and its receptor PDGFR beta to regulate development of micro-vasculature.

The integrity of vascular walls depends on the interaction between the outer sheath of mural cells and the inner endothelial cells. PDGFB-mediated signal transduction regulates mural-cell function, and is modulated by the interactions of PDGFB with PDGFR beta and various accessory factors. This prompted Weiss and colleagues to investigate a previous report that the expression of MT1-MMP specifically in mural cells is associated with the recruitment of these cells to developing vasculature.

Histological analysis showed that the aortae of young MT1-MMP^-/- mice were defective; but in culture, MT1-MMP^-/- and MT1-MMP^+/+ mural cells were visually indistinguishable. However, treating the MT1-MMP^-/- cells with various growth factors revealed defects in their growth and chemotactic responses, but only when PDGFB was used to stimulate the cells.

The levels of PDGFB and PDGFR beta proteins and the extent of their phosphorylation was comparable in wild-type and MT1-MMP^-/- cells. Moreover, MT1-MMP was found to bind PDGFR beta , both with and without PDGFB. However, the normal PDGFB signalling responses, such as increased active extracellular signal-regulated kinase 1/2 and AKT levels and changes in actin polymerization, were significantly reduced or absent in MT1-MMP^-/- cells.

The responses of MT1-MMP^-/- cells to PDGFB could be restored by the retroviral expression of wild-type MT1-MMP, but not of catalytically inactive MT1-MMP. Furthermore, in COS-1 cells (where MT1-MMP and PDGFR beta are usually undetectable) only co-expression of MT1-MMP and PDGFR beta could produce an optimal signalling response to PDGFB. So, catalytically active MT1-MMP is an important component of the PDGFB–PDGFR beta signalling complex.

Furthermore, the vascular morphology of MT1-MMP^-/- mice seems to phenocopy that of PDGFR beta mutants. Similarly, tissue explants from MT1-MMP^-/- mice mirror the wound-healing responses of Pdgfr^-/- cells from chimeric Pdgfr^-/- Pdgfr^+/+ mice.

So in mural cells, MT1-MMP is necessary for the propagation of signalling through PDGFB–PDGFR beta . This pathway is crucial in stabilizing the vasculature of growing tumours, so the discovery that MT1-MMP is required for this process has uncovered a potential target for therapeutics that could be used to control tumour vascularization.

Lesley Cunliffe

References

Lehti, K. et al. An MT1-MMP–PDGF receptor- axis regulates mural cell investment of the microvasculature. Genes Dev. 19, 979–991 (2005)