Invasion-promoting, membrane-tethered membrane type-1 matrix metalloproteinase (MT1-MMP) is known to play multiple key roles as a modifier of cell function. MT1-MMP, unlike any of the other twenty five known human MMPs, is closely associated with aggressive malignancies. There is consensus among scientists that membrane-tethered MT1-MMP is a key player in cell surface proteolytic events. We have, however, identified an MT1-MMP-mediated intracellular event that appears to herald the onset of malignant transformation. In its unorthodox, intracellular trafficking pathway, MT1-MMP traverses centrosomes. In centrosomes, MT1-MMP degrades an integral centrosomal protein, pericentrin, and causes chromosome instability, an early and accurate predictor of oncogenesis and malignant transformation. We suggest that MT1-MMP-induced chromatin instability represents a major element of malignant transformation. In addition, MT1-MMP proteolysis regulates the functionality of cell adhesion-signaling receptors, and governs the activation and the subsequent clearance of the soluble proteases from the extracellular milieu. The four aims, which we designed to gain a comprehensive understanding of MT1-MMP and which we are confident of reaching in the course of this program are:
Aim I -Determine the interactions of MT1-MMP with integrin alpha-v-beta3 which stimulate invasive tumor growth and angiogenesis;
Aim II -Determine the role of MT1-MMP in regulating the functionality of the LRP scavenger receptor and in the subsequent internalization of MMPs;
Aim III -Identify the mechanisms involved in the transport of newly synthesized MT1-MMP through the cell, its follow-up internalization into the intracellular storage compartment and its recycling to the plasma membrane;
Aim I V-Identify the proteolytic targets and the functional role of the centrosomal MT1-MMP in cell cycle events. The integrated result of the studies described herein will be a thorough understanding of the broad spectrum of roles played by this ubiquitous membrane-tethered metalloproteinase. Our program is based upon an integrated systems approach and involves biochemical, molecular/cell biological and computer modeling/bioinformatics studies. We will also conduct studies using tumor xenografts in immunodeficient mice to improve our essential knowledge of cell migration and invasion, tumor growth and neovascularization in vivo. Our program will also result in a greatly improved understanding of precisely how cells escape from their normal location and spread throughout the body. This valuable information will lead directly to the development of novel and efficient strategies for the detection, prognosis, and treatment of a broad range of pathologies.
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