Here, we demonstrate that: 1) progranulin is expressed at high levels in mesothelioma cell lines representative of various mesothelioma histopathological subtypes as compared to non-transformed mesothelial cells; 2) progranulin sustains the activation of the AKT and MAPK signaling pathways in mesothelioma cells, with progranulin signaling being mediated by EGFR, RYK and FAK; 3) progranulin modulates mesothelioma cell migration, invasion, adhesion and in vivo tumor growth; 4) progranulin regulates focal adhesion turnover by affecting FAK activation in a RYK-dependent manner. Here, RYK is linked to mesothelioma.