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Cytokines in immune regulation
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Published 8 November 2004. doi:10.1083/jcb.200403155
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 3, 469-478
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Article

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

Christopher C. Williams1, June G. Allison6, Gregory A. Vidal2, Matthew E. Burow3, Barbara S. Beckman4, Luis Marrero5, and Frank E. Jones1

1 Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center
2 Department of Structural and Cellular Biology, Tulane University Health Sciences Center, Tulane Cancer Center
3 Department of Medicine, Tulane University Health Sciences Center, Tulane Cancer Center
4 Department of Pharmacology, Tulane University Health Sciences Center, Tulane Cancer Center
5 Louisiana State University Health Sciences Center, Gene Therapy Program, The Morphology and Imaging Core Laboratory, New Orleans, LA 70112
6 Northshore High School, Saint Tammany School Board, Slidell, LA 70461

Correspondence to Frank E. Jones: fjones{at}tulane.edu

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 ß-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the ß-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin ß1 (HRG)-stimulated cells and both proteins bind to the endogenous ß-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.

C.C. Williams and J.G. Allison contributed equally to this work.

Abbreviations used in this paper: 4ICD, ERBB4 intracellular domain; ChIP, chromatin immunoprecipitation; dsRed, Discosoma red fluorescent protein; EGFR, EGF receptor; GAS, {gamma}-interferon activation sites; HRG, heregulin ß1; LMB, leptomycin B; Prl, prolactin; STAT, signal transducer and activator of transcription; TACE, TNF{alpha}-converting enzyme; YAP, yes-associated protein.


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