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Previously, we showed that pancreatic injury consisting of acinar cell damage+<jats:italic>\u03b2<\/jats:italic>-cell ablation led to islet cell transdifferentiation. Here, we report that the molecular mechanism for this requires activating protease-activated receptor-2 (PAR2), a G-protein-coupled receptor. PAR2 modulation was sufficient to induce islet cell transdifferentiation in the absence of<jats:italic>\u03b2<\/jats:italic>-cells. Its expression was modulated in an islet cell type-specific manner in murine and human type 1 diabetes (T1D). In addition to transdifferentiation, PAR2 regulated<jats:italic>\u03b2<\/jats:italic>-cell apoptosis in pancreatitis. PAR2\u2019s role in regeneration is broad, as mice lacking PAR2 had marked phenotypes in response to injury in the liver and in digit regeneration following amputation. 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