Molecular Scaffolds Direct MAPK Signaling Specificity

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DESCRIPTION (provided by applicant): Normal cellular function is dependent on the ability of environmental signals to elicit distinct responses through activation of specific cell surface receptors, and yet these signals often converge on the same members of the MAPK family. How can cells maintain specificity of signal transduction when so many different receptors ultimately activate the same enzyme? My previous work helped establish that components of the endocytotic machinery, (e.g. b-arrestin), can assemble scaffolding complexes that direct the subcellular localization, duration and outcome of MAPK activity. These studies investigate the mechanism by which these endosomal scaffolds can direct distinct cellular outcomes, by characterizing a molecular scaffold formed in response to protease-activated receptor-2 (PAR-2) that promotes chemotaxis by sequestering and prolonging MAPK activity at the leading edge and comparing it to one formed in response to a receptor that promotes nuclear translocation of MAPK and proliferation. We pose the following questions: 1) Does the PAR-2 endosomal scaffold sequester MAPK to a subcellular domain where it directs localized reorganization of the cytoskeleton? 2) Do receptor/b-arrestin interactions and molecular contacts within each endosomal scaffold and ultimately determine the outcome of receptor activation? 3) How does the endosomal scaffold control kinase activity in a specialized region of the cell? Understanding the mechanism by which endosomal scaffolds determine signaling specificity is important from a fundamental cell biological perspective as recent studies suggest this mechanism is utilized by a wide variety of receptors. Furthermore, the receptor on which this study focuses, PAR-2, is involved in a plethora of normal physiological and pathological processes; two areas studied in our laboratory are tumor metastasis and maintenance of colonic epithelial integrity. Therefore, understanding the molecular basis of PAR-2 signaling may ultimately lead to new targets for the treatment of metastasis and inflammatory bowel diseases.