CYR61 AND FISP12 ARE BOTH ECM-ASSOCIATED SIGNALING MOLECULES - ACTIVITIES, METABOLISM, AND LOCALIZATION DURING DEVELOPMENT

cyr61 and fisp12 are homologous immediate-early genes that are transcr iptionally activated upon growth factor stimulation in fibroblasts. Th eir gene products belong to an emerging family of secreted proteins wi th a high degree of sequence homology, including conservation of all 3 8 cysteine residues in their secreted portions. We have recently shown that Cyr61 is an extracellular matrix (ECM) signaling molecule that p romotes cell proliferation, migration, and adhesion. We describe herei n the first purification of the Fisp12 protein and we compare the acti vities of purified Cyr61 and Fisp12, their metabolism targeting, and t heir localization during development. Although Fisp12 is the mouse hom olog of the human connective tissue growth factor (CTGF), it has no de tectable mitogenic activity by itself Rather, Fisp12 enhances fibrobla st growth factor-induced DNA synthesis. The activities of Fisp12 and C yr61 are nearly indistinguishable in three cell types tested: fibrobla sts, endothelial, and epithelial cells. Both proteins are found in the ECM, although Cyr61 associates with the ECM more strongly and binds h eparin with higher affinity. Fisp12, but not Cyr61, is also found in t he culture medium, suggesting that Fisp12 might be able to act at a di stance from its site of secretion, whereas Cyr61 might act more locall y. Both secreted proteins are internalized and degraded through the ly sosomal pathway, suggesting interaction with cell surface receptors. B oth Cyr61 and Fisp12 are found in the placenta and the circulatory sys tem as detected by immunohistochemistry, whereas Cyr61, but not Fisp12 , is found in the skeletal and nervous systems. Fisp12, but not Cyr61, is found in secretory organs. Taken together, we propose that Cyr61 a nd Fisp12 are both signaling cell adhesion molecules that have similar or overlapping activities, and their differential sites of localizati on and targeting may dictate specificity in their biological roles. (C ) 1997 Academic Press.