Our results indicated that the binding of SH3BGRL to HER2 can activate HER2 phosphorylation at Y1196 and the downstream signaling to promote tumor cell proliferation and survival, regardless of EGF stimulation, uncovering that prior to ligand stimulation, SH3BGRL may promote HER2 to form dimers with other RGFR members. This evidence concerns the gene EGF and neoplasm.