Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways.
TGF-beta and BMP receptor kinases activate Smad transcription factors by C-terminal phosphorylation. We have identified a subsequent agonist-induced phosphorylation that plays a central dual role in Smad transcriptional activation and turnover. As receptor-activated Smads form transcriptional complexes, they are phosphorylated at an interdomain linker region by CDK8 and CDK9, which are components of transcriptional mediator and elongation complexes. These phosphorylations promote Smad transcriptional action, which in the case of Smad1 is mediated by the recruitment of YAP to the phosphorylated linker sites. An effector of the highly conserved Hippo organ size control pathway, YAP supports Smad1-dependent transcription and is required for BMP suppression of neural differentiation of mouse embryonic stem cells. The phosphorylated linker is ultimately recognized by specific ubiquitin ligases, leading to proteasome-mediated turnover of activated Smad proteins. Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-beta pathways.
Alarcón
Claudio
C
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Zaromytidou
Alexia-Ileana
AI
Xi
Qiaoran
Q
Gao
Sheng
S
Yu
Jianzhong
J
Fujisawa
Sho
S
Barlas
Afsar
A
Miller
Alexandria N
AN
Manova-Todorova
Katia
K
Macias
Maria J
MJ
Sapkota
Gopal
G
Pan
Duojia
D
Massagué
Joan
J
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D003260:Contact Inhibition; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D006801:Humans; D051379:Mice; D009929:Organ Size; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051785:Smad Proteins / Q000737:chemistry / Q000235:genetics*; D051898:Smad1 Protein / Q000235:genetics; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C467972:Cdk9 protein, mouse; D056850:Cyclin-Dependent Kinase 8; D042863:Cyclin-Dependent Kinase 9