Postdoctoral positions are available immediately to study the physiological and pathological roles of a novel signaling mechanism mediated by a matrix metalloproteinase.
Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, has been implicated in a variety of physiological and pathological processes. Unlike the other MMPs, whose genetic deficiency has minor phenotypic effects, the genetic deficiency of MT1-MMP causes severe defects in skeletal development with marked deceleration of postnatal growth, shortening of long bones, defective vascularization of the cartilage and delayed formation of secondary ossification centers. In addition, MT1-MMP-deficient mice show important defects in alveolar development and adult angiogenesis, and die by 3 weeks of age. It has been proposed that the phenotype of these mice results from the lack of the proteolytic activity of MT1-MMP. Ample experimental evidence has also shown that the proteolytic activity of MT1-MMP is required for tumor cell invasion and proliferation, and high levels of MT1-MMP are expressed by a variety of tumors. MT1-MMP forms a stoichiometric complex with its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2), which binds to the catalytic domain of MT1-MMP and inhibits its proteolytic activity. Our studies have shown that TIMP-2 binding to MT1-MMP induces activation of Extracellular signal-Regulated Kinase 1/2 (ERK1/2) by a mechanism independent of the MT1-MMP proteolytic domain and the inhibitory domain of TIMP-2. This effect involves TIMP-2 binding to a non-proteolytic domain of MT1-MMP and is mediated by the cytoplasmic tail of MT1-MMP. MT1-MMP-mediated activation of ERK1/2 upregulates cell migration and proliferation in vitro, and promotes tumor growth in vivo. These observations strongly advocate a very important role for the proteolysis-independent signaling mechanism we identified.
Our laboratory currently focuses on the development of the following projects:
1. Investigating the molecular mechanism by which TIMP-2 – MT1-MMP interaction activates intracellular signaling, and its role in tumor progression. We use molecular and cellular biology techniques to identify the region(s) of MT1-MMP and TIMP-2 that mediate their binding and ERK1/2 activation, characterize the mechanism of signal transduction from MT1-MMP to the ERK1/2 pathway, and determine the functional role of TIMP-2 - MT1-MMP interaction in tumor growth and metastasis in experimental in vivo models. The ultimate goal of this study is the development of inhibitors aimed to block MT1-MMP – TIMP-2 interaction and the generation of intracellular signaling that promotes tumor progression.
2. Generating a transgenic mouse that expresses a point mutation in the MT1-MMP cytoplasmic tail which abolishes the signaling capacity without affecting the proteolytic activity of MT1-MMP. We will then compare the phenotype of this mouse to those of wt and MT1-MMP null mice. We expect that expression of signaling-incompetent MT1-MMP will result in a phenotype that partially recapitulates the phenotype of MT1-MMP null mice. Therefore, the analysis of the phenotype of our mutant mice will allow us to understand the role of MT1-MMP-mediated signaling in development, normal physiology and pathology.
Expertise in basic molecular and cell biology, and protein biochemistry techniques is desirable for participation in both projects. These positions are open to US national and international candidates. Please contact:
Paolo Mignatti, MD
New York University School of Medicine
550 First Ave, NBV 15W16
New York, NY 10016
phone: 212-263-1478 / email: email@example.com