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Background  Grb2 (Growth factor receptor-bound protein 2) is a key adaptor protein in maintaining the ERK activity  via  linking Sos1 (Son of sevenless homolog 1) or other proteins to activated RTKs, such as EGFR. Currently, little knowledge is available concerning the post-translational modification (PTM) of Grb2 except for its phosphorylation. Since emerging evidences have highlighted the importance of SUMOylation (Small ubiquitin-related modifier), a reversible PTM, in modulating protein functions, we wondered if Grb2 could be SUMOylated and thereby influences its functions especially involved in the Ras/MEK/ERK pathway.    Methods  SUMOylation of Grb2 was analyzed with the  in vivo  SUMOylation assay using the Ni 2+ -NTA affinity pulldown and the  in vitro E.coli -based SUMOylation assay. To test the ERK activity and cell transformation, the murine fibroblast cell line NIH/3T3 and the murine colon cancer cell line CMT-93 were used for the experiments including Grb2 knockdown, ectopic re-expression, cell transformation and migration. Immunoprecipitation (IP) was employed for seeking proteins that interact with SUMO modified Grb2. Xenograft tumor model in mice was conducted to verify that Grb2 SUMOylation regulated tumorigenesis  in vivo .    Results  Grb2 can be SUMOylated by SUMO1 at lysine 56 (K 56 ), which is located in the linker region between the N-terminal SH3 domain and the SH2 domain. Knockdown of Grb2 reduced the ERK activity and suppressed cell motility and tumorigenesis  in vitro  and  in vivo , which were all rescued by stable ectopic re-expression of wild-type Grb2 but not the mutant Grb2 K56R . Furthermore, Grb2 SUMOylation at K 56  increased the formation of Grb2-Sos1 complex, which sequentially leads to the activation of Ras/MEK/MAPK pathway.    Conclusions  Our results provide evidences that Grb2 is SUMOylated  in vivo  and this modification enhances ERK activities  via  increasing the formation of Grb2-Sos1 complex, and may consequently promote cell motility, transformation and tumorigenesis.

SUMOylation of Grb2 enhances the ERK activity by increasing its binding with Sos1