Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription.
Src/Yes tyrosine kinase signaling contributes to the regulation of bone homeostasis and inhibits osteoblast activity. Here we show that the endogenous Yes-associated protein (YAP), a mediator of Src/Yes signaling, interacts with the native Runx2 protein, an osteoblast-related transcription factor, and suppresses Runx2 transcriptional activity in a dose-dependent manner. Runx2, through its PY motif, recruits YAP to subnuclear domains in situ and to the osteocalcin (OC) gene promoter in vivo. Inhibition of Src/Yes kinase blocks tyrosine phosphorylation of YAP and dissociates endogenous Runx2-YAP complexes. Consequently, recruitment of the YAP co-repressor to subnuclear domains is abrogated and expression of the endogenous OC gene is induced. Our results suggest that Src/Yes signals are integrated through organization of Runx2-YAP transcriptional complexes at subnuclear sites to attenuate skeletal gene expression.
Zaidi
Sayyed K
SK
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655-0106, USA.
Sullivan
Andrew J
AJ
Medina
Ricardo
R
Ito
Yoshiaki
Y
van Wijnen
Andre J
AJ
Stein
Janet L
JL
Lian
Jane B
JB
Stein
Gary S
GS
D020816:Amino Acid Motifs; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D018797:Cell Cycle Proteins; D002843:Chromatin; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C493709:RUNX2 protein, human; C493717:Runx2 protein, rat; D015534:Trans-Activators; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D015675:Osteocalcin; D014443:Tyrosine; D019061:src-Family Kinases