title: Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex: IMPLICATION OF A NOVEL MDMX SER-314 PHOSPHOSITE.
abstract: Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes. Using a phospho-proteomics approach, we functionally identified a novel Her4-induced posttranslational modification on MDMX at Ser-314, a putative phosphorylation site for the CDK4/6 kinase. Remarkably, inhibition of Ser-314 phosphorylation either with Ser-to-Ala substitution or with a specific inhibitor of CDK4/6 kinase blocked Her4-induced stabilization of MDMX-MDM2 and rescued p53 activity. Our study offers insights into the mechanisms of deregulated RTK-induced carcinogenesis and provides the basis for the use of inhibitors targeting RTK-mediated signals for p53 restoration.
authors: From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115.
authors: Casimiro
authors: C
authors: Gerarduzzi
authors: From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115.
authors: Anna
authors: A
authors: de Polo
authors: From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115.
authors: Xue-Song
authors: XS
authors: Liu
authors: From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115.
authors: Manale
authors: M
authors: El Kharbili
authors: From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115.
authors: John B
authors: JB
authors: Little
authors: From the John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115 zyuan@hsph.harvard.edu.
authors: Zhi-Min
authors: ZM
authors: Yuan
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: ErbB4; MDMX; breast cancer; cyclin-dependent kinase (CDK); mouse double minute 2 homolog (MDM2); p53; radiotherapy; receptor tyrosine kinase