A Smad action turnover switch operated by WW domain readers of a phosphoserine code (original) (raw)

  1. Nina Goerner1,5,
  2. Alexia-Ileana Zaromytidou2,
  3. Qiaoran Xi2,
  4. Albert Escobedo1,
  5. Joan Massagué2,3,6,7 and
  6. Maria J. Macias1,4,6
  7. 1Structural and Computational Biology Programme, Institute for Research in Biomedicine, 08028 Barcelona, Spain;
  8. 2Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;
  9. 3Howard Hughes Medical Institute (HHMI), Chevy Chase, Maryland 20185, USA;
  10. 4Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
  11. ↵5 These authors contributed equally to this work.
  12. ↵6 These authors contributed equally to this work.

Abstract

When directed to the nucleus by TGF-β or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events—Smad activation first and destruction later—and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-β pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-β signal delivery to turnover of the Smad signal transducers.

Footnotes

Freely available online through the Genes & Development Open Access option.