The role of CCN5/WISP2 protein in pancreatic islets

Abstract In search of direct targets of IGF-I action, we discovered CCN5/WISP2 as a novel protein expressed in pancreatic β-cells. As a member of Cyr61 (connective tissue growth factor in human), CTGF (cysteine rich 61, in mouse), and Nov (nephroblastoma overexpressed, in chicken) family, IGF-I together with Wnt signaling stimulate its expression. When overexpressed in insulinoma cells, CCN5 promotes cell proliferation and cell survival against streptozotocin-induced cell death. The cell proliferation effect seems to be caused by AKT phosphorylation and increased cyclin D1 level. These properties resemble that of CCN2/CTGF, another isoform of the CCN family, although CCN5 is the only one within the family of six proteins that lacks the C-terminal repeat. Treatment of primary mouse islets with recombinant CCN5 protein produced similar effects, indicating either being produced as a matricellular protein or a secreted growth factor, CCN5 stimulate β-cell proliferation and regeneration in a paracrine fashion. This review also discusses its regulation by estrogen and involvement in angiogenesis and tumorigenesis.