Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment.
Heregulin activation of the endogenous receptor tyrosine kinase ErbB-4 in ZR-75-1 breast cancer cells provokes tyrosine phosphorylation of Hdm2 in a manner that is sensitive to inhibition of alpha- or gamma-secretase activity, indicating that liberation of the tyrosine kinase intracellular domain (ICD) fragment is required. Similar results are obtained when Erbb-4 is exogenously expressed in 32D cells, which do not otherwise express any ErbB family members. Expression of the ErbB-4 ICD fragment leads to its constitutive association with Mdm2 and tyrosine phosphorylation of Mdm2, a protein that is predominantly localized in the nucleus and that regulates p53 levels. When the ErbB-4 ICD fragment was expressed in H1299 cells, it promoted Hdm2 ubiquitination and increased the levels of p53 and p21, a transcriptional target of p53. In addition, expression of the ICD fragment increased p53 activity toward the p21 promoter in a luciferase reporter assay.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Rajeswara Rao
RR
Arasada
Graham
G
Carpenter
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002460:Cell Line; D010450:Endopeptidases; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D066247:Receptor, ErbB-4; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D020890:Neuregulin-1; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C087230:heregulin beta1; D014443:Tyrosine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human