Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs
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Animals
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Chromatin / metabolism
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Core Binding Factor Alpha 1 Subunit
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Humans
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Osteoblasts / metabolism
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Osteocalcin / genetics
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Osteocalcin / metabolism
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Phosphorylation
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Rats
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factor AP-2
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tyrosine / metabolism*
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / physiology
Substances
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Cell Cycle Proteins
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Chromatin
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Core Binding Factor Alpha 1 Subunit
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DNA-Binding Proteins
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Nuclear Proteins
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RUNX2 protein, human
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Runx2 protein, rat
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Trans-Activators
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Transcription Factor AP-2
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Transcription Factors
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YY1AP1 protein, human
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Osteocalcin
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Tyrosine
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src-Family Kinases