The activity of the E3 ligase, Smurf2, is antagonized by an intra-molecular, auto-inhibitory interaction between its C2 and Hect domains. Relief of Smurf2 auto-inhibition is induced by TGFβ and is mediated by the inhibitory SMAD, Smad7. In a proteomic screen for endo-membrane interactants of the RING-domain E3 ligase, Rnf11, we identified Smurf2, among a cohort of Hect E3 ligases previously implicated in TGFβ signaling. Reconstitution of the Smurf2/Rnf11 complex in vitro unexpectedly revealed robust Smurf2 E3 ligase activity, with biochemical properties previously restricted to the Smurf2/Smad7 complex. Using in vitro binding assays, we find that Rnf11 can directly compete with Smad7 for Smurf2 and that binding is mutually exclusive and dependent on a proline-rich domain. Moreover, we found that co-expression of Rnf11 and Smurf2 dramatically reduced Smurf2 ubiquitylation in the cell. This effect is strictly dependent on complex formation and sorting determinants that regulate the association of Rnf11 with membranes. Rnf11 is over-expressed in certain tumors, and, importantly, we find that depletion of this protein down-regulated gene expression of several TGFβ-responsive genes, dampened cell proliferation, and dramatically reduced cell migration in response to TGFβ. Our data suggest for the first time that choice of binding partners for Smurf2 can sustain or repress TGFβ signaling and Rnf11 may promote TGFβ-induced cell migration.
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