title: A Smad action turnover switch operated by WW domain readers of a phosphoserine code.
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.
authors.affiliation: Structural and Computational Biology Programme, Institute for Research in Biomedicine, Barcelona, Spain.
authors.forename: Eric
authors.initials: E
authors.lastname: Aragón
authors.forename: Nina
authors.initials: N
authors.lastname: Goerner
authors.forename: Alexia-Ileana
authors.initials: AI
authors.lastname: Zaromytidou
authors.forename: Qiaoran
authors.initials: Q
authors.lastname: Xi
authors.forename: Albert
authors.initials: A
authors.lastname: Escobedo
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Macias
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051785:Smad Proteins / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009687:Nuclear Proteins; D051785:Smad Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C456659:YY1AP1 protein, human; D010768:Phosphoserine; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase