Post-translational modifications: The active TGF-β receptor is sumoylated

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Transforming growth factor-β receptor type I is sumoylated, which regulates Smad3 activation and affects invasion and metastasis.

Transforming growth factor-β (TGF-β) signaling is propagated by the heterotetrameric TGF-β receptor, which consists of two type I (TβRI) and two type II (TβRII) serine/threonine kinases. Following ligand binding, TβRII transphosphorylates TβRI, which stimulates additional trans- and autophosphorylation and phosphorylates the downstream effector molecules Smad2/Smad3. TβRI/TβRII are known to undergo ubiquitination to promote their degradation. In Nature Cell Biology, Kang et al. now report that active, phosphorylated TβRI is also sumoylated, which facilitates Smad3 binding and TGF-β signaling..

SUMO (small ubiquitin-like modifier) is a small molecule that is post-translationally added to many nuclear proteins to regulate transcription and nuclear transport. The authors found that TβRI, but not other TGF-β receptor family members, was specifically sumoylated in vitro and in vivo. TGF-β increased sumoylation of the receptor in vivo, suggesting that the active form of the receptor is preferentially sumoylated. Indeed, constitutively active TβRI was sumoylated more efficiently than wild-type TβRI, and pharmacologic inhibition of TβRI kinase activity, or dephosphorylation of TβRI, decreased sumoylation. Similarly, a kinase-dead TβRI^K230R or TβRII^K277R mutation prevented efficient sumoylation.

Site-directed mutagenesis showed that Lys 389, which lies close to the Smad3 binding site, was required for sumoylation, as a TβRI^K389R mutant was not sumoylated. Furthermore, the TβRI^K389R mutant did not robustly phosphorylate Smad3 in vitro and was unable to stimulate transcription of Smad-responsive genes. Lack of sumoylation affected TGF-β signaling in vivo, as Tgfbr1^-/- cells that expressed exogenous TβRI showed decreased proliferation in response to TGF-β, whereas cells that expressed TβRI^K389R were not affected. Sumoylation of TβRI also appears to contribute to invasion and metastasis. HRas-transformed Tgfbr1^-/- mouse embryonic fibroblasts (MEFs) that expressed TβRI^K389R were less invasive in vitro and formed fewer, smaller lung metastases in mice than MEFs expressing wild-type TβRI. Thus, sumoylation of TβRI appears to regulate its biological activities in part by potentiating Smad3 binding. However, it is not yet know which SUMO-conjugating enzymes regulate TβRI sumoylation, or how activation of TβRI regulates this process.

These studies define a role for TβRI sumoylation in regulating invasion and metastatic growth. Interestingly, a TGFBR1 mutant linked to breast and head-and-neck cancer metastases was a poor substrate for sumoylation both in vitro and in vivo. This mutant also showed limited Smad-mediated transcriptional response to TGF-β. Whether this mutation provides a competitive advantage by stimulating invasion and metastasis but disrupting other aspects of TβRI signaling, such as Smad-independent signaling pathways, awaits further investigation.

Emily J. Chenette
Signaling Gateway

References

Kang, J. S., Saunier, E. F., Akhurst, R. J. and Derynck, R. The type I TGF-β receptor is covalently modified and regulated by sumoylation. Nature Cell Biology 10, 654-664 (2008) | Article | PubMed |
Miyazono, K., Kamiya, Y. and Miyazawa, K. SUMO amplifies TGF-β signalling. Nature Cell Biology 10, 635-637 (2008) | Article | PubMed |