Here, through a combination of in vitro and in vivo methods, we fully elucidated that SH2B3 bound to JAK2 and SHP2 to suppress JAK2/STAT3 and SHP2/Grb2/PI3K/AKT signaling pathways respectively, resulting in inhibition on anoikis resistance, EMT, and cancer cell proliferation, migration, and invasion. This evidence concerns the gene PTPN11 and cancer.