Identification of Alternative Substrates of Pregnancy-Associated Plasma Protein-A

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DESCRIPTION (provided by applicant): Pregnancy Associated Plasma Protein-A (PAPP-A) was identified in 1974 as one of four protein markers in normal human pregnancy serum. PAPP-A is a metalloprotease that cleaves Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) into 2 fragments. This cleavage causes the release of IGFs from IGFBP-4 sequestration and allows the Insulinlike Growth Factors (IGFs) to bind to the cell surface IGF receptor. Thus PAPP-A is an important regulator of IGF bioavailability. Since this discovery, PAPP-A has been implicated in a variety of biological systems including fetal development, bone remodeling, wound healing, atherosclerosis, acute coronary syndrome, aging and cancer. In spite of the fact that PAPP-A has been aggressively studied in the past, there is very little evidence to directly implicate PAPP-A or it's proteolytic activity in biological systems other than the IGFs. The purpose of this application is to probe samples from mouse PAPP-A null and wild-type tissue using open ended proteomic tools in order to determine if PAPP-A cleaves proteins other than IGFBP-4 in biological systems. Specifically we will use two dimensional gel electrophoresis and liquid chromatography to compare the protein expression pattern of the PAPP-A null tissue against the protein expression pattern of the wild-type tissue. Any protein expression differences discovered are likely to be the direct or indirect result of PAPP-A proteolytic activity. The proteins with altered expression will be identified. The information gained from the identification of these proteins will suggest novel biological roles for PAPP-A and may lead to the direct link between PAPP-A and human diseases. PUBLIC HEALTH RELEVANCE: Pregnancy-Associated Plasma Protein-A (PAPP-A) is an important modulator of Insulin- like Growth Factor signaling. PAPP-A has been implicated in several human biological systems, including atherosclerosis, acute coronary syndrome, aging and cancer, however direct evidence of PAPP-A proteolytic activity in these systems is lacking. This goal of this application is to investigate and discover a direct link between PAPP-A proteolytic activity and known or novel biological systems.