In this study, we found that SUMOylation of Shp2 promoted the activation of ERK signaling via facilitating the formation of Shp2-Gab1 (Grb2-associated binder-1) complex and thereby accelerated HCC cell and tumor growth, which presented a novel regulatory mechanism for Shp2 in regulation of HCC development. Here, PTPN11 is linked to hepatocellular carcinoma.