The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone

Christopher C. Williams, June G. Allison, Gregory Vidal, Matthew E. Burow, Barbara S. Beckman, Luis Marrero, Frank E. Jones

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

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 β-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the β-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin β1 (HRG)-stimulated cells and both proteins bind to the endogenous β-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.

Original languageEnglish (US)
Pages (from-to)469-478
Number of pages10
JournalJournal of Cell Biology
Volume167
Issue number3
DOIs
StatePublished - Nov 8 2004
Externally publishedYes

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Receptor Protein-Tyrosine Kinases
Caseins
Transcription Factors
Gene Expression
STAT5 Transcription Factor
Neuregulin-1
Breast Neoplasms
Essential Genes
Cytoplasmic and Nuclear Receptors
Signal Transduction
Carrier Proteins
Milk
Breast
Epithelium
Cell Line
Proteins

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. / Williams, Christopher C.; Allison, June G.; Vidal, Gregory; Burow, Matthew E.; Beckman, Barbara S.; Marrero, Luis; Jones, Frank E.

In: Journal of Cell Biology, Vol. 167, No. 3, 08.11.2004, p. 469-478.

Research output: Contribution to journalArticle

Williams, Christopher C. ; Allison, June G. ; Vidal, Gregory ; Burow, Matthew E. ; Beckman, Barbara S. ; Marrero, Luis ; Jones, Frank E. / The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. In: Journal of Cell Biology. 2004 ; Vol. 167, No. 3. pp. 469-478.
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