METALLOPROTEASE DISINTEGRIN MDC9

Sloan-Kettering Institute For Cancer Res, New York NY

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Abstract

The long term objective is to understand the function of a new protein family, termed metalloprotease-disintegrins, in cell-cell and cell- matrix interactions. Metalloprotease-disintegrins (also referred to as MDC proteins or ADAMs) are a family of membrane anchored glycoproteins that are closely related to soluble snake venom integrin ligands and metalloproteases. Metalloprotease-disintegrin proteins have been implicated in fertilization, in muscle cell binding and fusion, in processing of the pro-inflammatory cytokine TNFalpha, and in the cleavage and activation of Notch. The general strategy is to focus on one metalloprotease-disintegrin protein, termed MDC9, which has a catalytically active metalloprotease domain, cytoplasmic signaling motifs such as SH3 ligand domains, and is expressed in all developmental stages and tissues analyzed to date. The specific aims of the present proposal are: 1) Analysis of the effects of a targeted deletion of MDC9 on mouse development and in the adult animal. 2) Identification of substrates of the MDC9 metalloprotease domain using embryonic stem cells and somatic cells lacking MDC9. 3) Identification of a receptor for MDC9, which we predict is a member of the integrin family, and search for extracellular interactions with other proteins. 4) Evaluation of the role of three candidate MDC9 cytoplasmic domain interacting proteins, identified in a yeast two hybrid screen, in regulating the MDC9 metalloprotease activity and/or a role in cell differentiation. These studies are expected to provide important new insights into the function of MDC9, and at the same time shed light on the role of other metalloprotease- disintegrin proteins in cell-cell interactions. In general, proteins that mediate cell adhesion or that function in specific proteolytic processing events are known to mediate critical aspects of development, and to be involved in the pathogenesis of diseases including cancer and metastasis. Because metalloprotease-disintegrins have been linked to proteolytic processing events such as cytokine shedding and protein ectodomain processing, and to functions in cell adhesion, it is anticipated that the further analysis of the widely expressed MDC9 will provide exciting new insights into the function of this protein in development, and in normal and pathological cell physiology.