The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone.
In the lactating breast, ERBB4 localizes to the nuclei of secretory epithelium while regulating activities of the signal transducer and activator of transcription (STAT) 5A transcription factor essential for milk-gene expression. We have identified an intrinsic ERBB4 NLS (residues 676-684) within the ERBB4 intracellular domain (4ICD) that is essential for nuclear accumulation of 4ICD. To determine the functional significance of 4ICD nuclear translocation in a physiologically relevant system, we have demonstrated that cotransfection of ERBB4 and STAT5A in a human breast cancer cell line stimulates beta-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the beta-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin beta 1 (HRG)-stimulated cells and both proteins bind to the endogenous beta-casein promoter in T47D breast cancer cells. Together, our results establish a novel molecular mechanism of transmembrane receptor signal transduction involving nuclear cotranslocation of the receptor intracellular domain and associated transcription factor. Subsequent binding of the two proteins at transcription factor target promoters results in activation of gene expression.
Williams
Christopher C
CC
Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA 70112, USA.
Allison
June G
JG
Vidal
Gregory A
GA
Burow
Matthew E
ME
Beckman
Barbara S
BS
Marrero
Luis
L
Jones
Frank E
FE
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000473:pathology; D002364:Caseins / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000502:physiology*; D020890:Neuregulin-1 / Q000378:metabolism; D019913:Nuclear Localization Signals; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D066247:Receptor, ErbB-4; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins
D002364:Caseins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D018832:Molecular Chaperones; D020890:Neuregulin-1; D019913:Nuclear Localization Signals; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C087230:heregulin beta1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4