Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Cell Biol. 167 (3): 469-478

Copyright © 2004 by the Rockefeller University Press.

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

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 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.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-Src.
K. Ishibashi, Y. Fukumoto, H. Hasegawa, K. Abe, S. Kubota, K. Aoyama, S. Kubota, Y. Nakayama, and N. Yamaguchi (2013)
J. Cell Sci. 126, 625-637
   Abstract »    Full Text »    PDF »
Cell Responses to Growth Factors: The Role of Receptor Tyrosine Kinase Intracellular Domain Fragments.
G. Carpenter and A. Pozzi (2012)
Science Signaling 5, pe42
   Abstract »    Full Text »    PDF »
Protein Inhibitor of Activated STAT3 (PIAS3) Protein Promotes SUMOylation and Nuclear Sequestration of the Intracellular Domain of ErbB4 Protein.
M. Sundvall, A. Korhonen, K. Vaparanta, J. Anckar, K. Halkilahti, Z. Salah, R. I. Aqeilan, J. J. Palvimo, L. Sistonen, and K. Elenius (2012)
J. Biol. Chem. 287, 23216-23226
   Abstract »    Full Text »    PDF »
Interaction with ErbB4 Promotes Hypoxia-inducible Factor-1{alpha} Signaling.
I. Paatero, A. Jokilammi, P. T. Heikkinen, K. Iljin, O.-P. Kallioniemi, F. E. Jones, P. M. Jaakkola, and K. Elenius (2012)
J. Biol. Chem. 287, 9659-9671
   Abstract »    Full Text »    PDF »
Jumonji/ARID1 B (JARID1B) Protein Promotes Breast Tumor Cell Cycle Progression through Epigenetic Repression of MicroRNA let-7e.
D. Mitra, P. M. Das, F. C. Huynh, and F. E. Jones (2011)
J. Biol. Chem. 286, 40531-40535
   Abstract »    Full Text »    PDF »
Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3.
C. R. Degnin, M. B. Laederich, and W. A. Horton (2011)
Mol. Biol. Cell 22, 3861-3873
   Abstract »    Full Text »    PDF »
Neuregulin Receptor ErbB4 Functions as a Transcriptional Cofactor for the Expression of Surfactant Protein B in the Fetal Lung.
K. Zscheppang, T. Dork, A. Schmiedl, F. E. Jones, and C. E. L. Dammann (2011)
45, 761-767
   Abstract »    Full Text »    PDF »
HMGN2 Inducibly Binds a Novel Transactivation Domain in Nuclear PRLr to Coordinate Stat5a-Mediated Transcription.
A. A. Fiorillo, T. R. Medler, Y. B. Feeney, Y. Liu, K. L. Tommerdahl, and C. V. Clevenger (2011)
Mol. Endocrinol. 25, 1550-1564
   Abstract »    Full Text »    PDF »
Ectodomain shedding and remnant peptide signalling of EGFRs and their ligands.
S. Higashiyama, D. Nanba, H. Nakayama, H. Inoue, and S. Fukuda (2011)
J. Biochem. 150, 15-22
   Abstract »    Full Text »    PDF »
Interactions of ErbB4 and Kap1 Connect the Growth Factor and DNA Damage Response Pathways.
M. Gilmore-Hebert, R. Ramabhadran, and D. F. Stern (2010)
Mol. Cancer Res. 8, 1388-1398
   Abstract »    Full Text »    PDF »
Presenilin/{gamma}-Secretase Cleaves CD46 in Response to Neisseria Infection.
N. J. Weyand, C. M. Calton, D. L. Higashi, K. J. Kanack, and M. So (2010)
J. Immunol. 184, 694-701
   Abstract »    Full Text »    PDF »
Nuclear Translocation of the Epidermal Growth Factor Receptor Family Membrane Tyrosine Kinase Receptors.
S.-C. Wang and M.-C. Hung (2009)
Clin. Cancer Res. 15, 6484-6489
   Abstract »    Full Text »    PDF »
ErbB4 Splice Variants Cyt1 and Cyt2 Differ by 16 Amino Acids and Exert Opposing Effects on the Mammary Epithelium In Vivo.
R. S. Muraoka-Cook, M. A. Sandahl, K. E. Strunk, L. C. Miraglia, C. Husted, D. M. Hunter, K. Elenius, L. A. Chodosh, and H. S. Earp III (2009)
Mol. Cell. Biol. 29, 4935-4948
   Abstract »    Full Text »    PDF »
An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance.
D. Mitra, M. J. Brumlik, S. U. Okamgba, Y. Zhu, T. T. Duplessis, J. G. Parvani, S. M. Lesko, E. Brogi, and F. E. Jones (2009)
Mol. Cancer Ther. 8, 2152-2162
   Abstract »    Full Text »    PDF »
Transcriptional Interaction of an Estrogen Receptor Splice Variant and ErbB4 Suggests Convergence in Gene Susceptibility Pathways in Schizophrenia.
J. Wong and C. S. Weickert (2009)
J. Biol. Chem. 284, 18824-18832
   Abstract »    Full Text »    PDF »
A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis.
K. Pedersen, P.-D. Angelini, S. Laos, A. Bach-Faig, M. P. Cunningham, C. Ferrer-Ramon, A. Luque-Garcia, J. Garcia-Castillo, J. L. Parra-Palau, M. Scaltriti, et al. (2009)
Mol. Cell. Biol. 29, 3319-3331
   Abstract »    Full Text »    PDF »
Somatic Mutations of ErbB4: SELECTIVE LOSS-OF-FUNCTION PHENOTYPE AFFECTING SIGNAL TRANSDUCTION PATHWAYS IN CANCER.
D. Tvorogov, M. Sundvall, K. Kurppa, M. Hollmen, S. Repo, M. S. Johnson, and K. Elenius (2009)
J. Biol. Chem. 284, 5582-5591
   Abstract »    Full Text »    PDF »
The E3 Ubiquitin Ligase WWP1 Selectively Targets HER4 and Its Proteolytically Derived Signaling Isoforms for Degradation.
S.-M. Feng, R. S. Muraoka-Cook, D. Hunter, M. A. Sandahl, L. S. Caskey, K. Miyazawa, A. Atfi, and H. S. Earp III (2009)
Mol. Cell. Biol. 29, 892-906
   Abstract »    Full Text »    PDF »
Prolactin and ErbB4/HER4 Signaling Interact via Janus Kinase 2 to Induce Mammary Epithelial Cell Gene Expression Differentiation.
R. S. Muraoka-Cook, M. Sandahl, D. Hunter, L. Miraglia, and H. S. Earp III (2008)
Mol. Endocrinol. 22, 2307-2321
   Abstract »    Full Text »    PDF »
All EGF(ErbB) receptors have preformed homo- and heterodimeric structures in living cells.
R.-H. Tao and I. N. Maruyama (2008)
J. Cell Sci. 121, 3207-3217
   Abstract »    Full Text »    PDF »
The HER4/4ICD Estrogen Receptor Coactivator and BH3-Only Protein Is an Effector of Tamoxifen-Induced Apoptosis.
A. Naresh, A. D. Thor, S. M. Edgerton, K. C. Torkko, R. Kumar, and F. E. Jones (2008)
Cancer Res. 68, 6387-6395
   Abstract »    Full Text »    PDF »
ErbB4 Isoforms Selectively Regulate Growth Factor induced Madin-Darby Canine Kidney Cell Tubulogenesis.
F. Zeng, M.-Z. Zhang, A. B. Singh, R. Zent, and R. C. Harris (2007)
Mol. Biol. Cell 18, 4446-4456
   Abstract »    Full Text »    PDF »
Association of Wwox with ErbB4 in Breast Cancer.
R. I. Aqeilan, V. Donati, E. Gaudio, M. S. Nicoloso, M. Sundvall, A. Korhonen, J. Lundin, J. Isola, M. Sudol, H. Joensuu, et al. (2007)
Cancer Res. 67, 9330-9336
   Abstract »    Full Text »    PDF »
The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.
J. Omerovic, L. Santangelo, E. M.-R. Puggioni, J. Marrocco, C. Dall'Armi, C. Palumbo, F. Belleudi, L. Di Marcotullio, L. Frati, M.-R. Torrisi, et al. (2007)
FASEB J 21, 2849-2862
   Abstract »    Full Text »    PDF »
The HER4 Cytoplasmic Domain, But Not Its C Terminus, Inhibits Mammary Cell Proliferation.
S.-M. Feng, C. I. Sartor, D. Hunter, H. Zhou, X. Yang, L. S. Caskey, R. Dy, R. S. Muraoka-Cook, and H. S. Earp III (2007)
Mol. Endocrinol. 21, 1861-1876
   Abstract »    Full Text »    PDF »
Latent membrane protein 1-induced EGFR signalling is negatively regulated by TGF{alpha} prior to neoplasia.
C. T. Charalambous, A. Hannigan, P. Tsimbouri, G. M. McPhee, and J. B. Wilson (2007)
Carcinogenesis 28, 1839-1848
   Abstract »    Full Text »    PDF »
HER4 D-Box Sequences Regulate Mitotic Progression and Degradation of the Nuclear HER4 Cleavage Product s80HER4.
K. E. Strunk, C. Husted, L. C. Miraglia, M. Sandahl, W. A. Rearick, D. M. Hunter, H. S. Earp III, and R. S. Muraoka-Cook (2007)
Cancer Res. 67, 6582-6590
   Abstract »    Full Text »    PDF »
Matrix Metalloproteinase 7 Mediates Mammary Epithelial Cell Tumorigenesis through the ErbB4 Receptor.
C. C. Lynch, T. Vargo-Gogola, M. D. Martin, B. Fingleton, H. C. Crawford, and L. M. Matrisian (2007)
Cancer Res. 67, 6760-6767
   Abstract »    Full Text »    PDF »
Bone Microenvironment and Androgen Status Modulate Subcellular Localization of ErbB3 in Prostate Cancer Cells.
C.-J. Cheng, X.-c. Ye, F. Vakar-Lopez, J. Kim, S.-M. Tu, D.-T. Chen, N. M. Navone, L.-Y. Yu-Lee, S.-H. Lin, and M. C-T. Hu (2007)
Mol. Cancer Res. 5, 675-684
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor (EGF) Receptor Ligands in the Chicken Ovary: I. Evidence for Heparin-Binding EGF-Like Growth Factor (HB-EGF) as a Potential Oocyte-Derived Signal to Control Granulosa Cell Proliferation and HB-EGF and Kit Ligand Expression.
Y. Wang, J. Li, C. Ying Wang, A. H. Yan Kwok, and F. C. Leung (2007)
Endocrinology 148, 3426-3440
   Abstract »    Full Text »    PDF »
Characterization of a Novel Tripartite Nuclear Localization Sequence in the EGFR Family.
S.-C. Hsu and M.-C. Hung (2007)
J. Biol. Chem. 282, 10432-10440
   Abstract »    Full Text »    PDF »
Rac1 and a GTPase-activating protein, MgcRacGAP, are required for nuclear translocation of STAT transcription factors.
T. Kawashima, Y. C. Bao, Y. Nomura, Y. Moon, Y. Tonozuka, Y. Minoshima, T. Hatori, A. Tsuchiya, M. Kiyono, T. Nosaka, et al. (2006)
J. Cell Biol. 175, 937-946
   Abstract »    Full Text »    PDF »
Heregulin-Dependent Delay in Mitotic Progression Requires HER4 and BRCA1.
R. S. Muraoka-Cook, L. S. Caskey, M. A. Sandahl, D. M. Hunter, C. Husted, K. E. Strunk, C. I. Sartor, W. A. Rearick Jr., W. McCall, M. K. Sgagias, et al. (2006)
Mol. Cell. Biol. 26, 6412-6424
   Abstract »    Full Text »    PDF »
ErbB-4 s80 Intracellular Domain Abrogates ETO2-dependent Transcriptional Repression.
B. Linggi and G. Carpenter (2006)
J. Biol. Chem. 281, 25373-25380
   Abstract »    Full Text »    PDF »
The Intracellular Domain of ErbB4 Induces Differentiation of Mammary Epithelial Cells.
R. S. Muraoka-Cook, M. Sandahl, C. Husted, D. Hunter, L. Miraglia, S.-m. Feng, K. Elenius, and H. S. Earp III (2006)
Mol. Biol. Cell 17, 4118-4129
   Abstract »    Full Text »    PDF »
Coregulation of Estrogen Receptor by ERBB4/HER4 Establishes a Growth-Promoting Autocrine Signal in Breast Tumor Cells.
Y. Zhu, L. L. Sullivan, S. S. Nair, C. C. Williams, A. K. Pandey, L. Marrero, R. K. Vadlamudi, and F. E. Jones (2006)
Cancer Res. 66, 7991-7998
   Abstract »    Full Text »    PDF »
Characterization of the Archaeal Thermophile Sulfolobus Turreted Icosahedral Virus Validates an Evolutionary Link among Double-Stranded DNA Viruses from All Domains of Life.
W. S. A. Maaty, A. C. Ortmann, M. Dlakic, K. Schulstad, J. K. Hilmer, L. Liepold, B. Weidenheft, R. Khayat, T. Douglas, M. J. Young, et al. (2006)
J. Virol. 80, 7625-7635
   Abstract »    Full Text »    PDF »
The ERBB4/HER4 Intracellular Domain 4ICD Is a BH3-Only Protein Promoting Apoptosis of Breast Cancer Cells..
A. Naresh, W. Long, G. A. Vidal, W. C. Wimley, L. Marrero, C. I. Sartor, S. Tovey, T. G. Cooke, J. M.S. Bartlett, and F. E. Jones (2006)
Cancer Res. 66, 6412-6420
   Abstract »    Full Text »    PDF »
Proteolytic Cleavage and Phosphorylation of a Tumor-associated ErbB4 Isoform Promote Ligand-independent Survival and Cancer Cell Growth.
J. A. Maatta, M. Sundvall, T. T. Junttila, L. Peri, V. J. O. Laine, J. Isola, M. Egeblad, and K. Elenius (2006)
Mol. Biol. Cell 17, 67-79
   Abstract »    Full Text »    PDF »
Radiation-induced Epidermal Growth Factor Receptor Nuclear Import Is Linked to Activation of DNA-dependent Protein Kinase.
K. Dittmann, C. Mayer, B. Fehrenbacher, M. Schaller, U. Raju, L. Milas, D. J. Chen, R. Kehlbach, and H. P. Rodemann (2005)
J. Biol. Chem. 280, 31182-31189
   Abstract »    Full Text »    PDF »
ERBB4/HER4 Potentiates STAT5A Transcriptional Activity by Regulating Novel STAT5A Serine Phosphorylation Events.
D. E. Clark, C. C. Williams, T. T. Duplessis, K. L. Moring, A. R. Notwick, W. Long, W. S. Lane, I. Beuvink, N. E. Hynes, and F. E. Jones (2005)
J. Biol. Chem. 280, 24175-24180
   Abstract »    Full Text »    PDF »
Presenilin-dependent {gamma}-Secretase Processing Regulates Multiple ERBB4/HER4 Activities.
G. A. Vidal, A. Naresh, L. Marrero, and F. E. Jones (2005)
J. Biol. Chem. 280, 19777-19783
   Abstract »    Full Text »    PDF »
Growth Hormone Receptor Is a Target for Presenilin-dependent {gamma}-Secretase Cleavage.
J. W. Cowan, X. Wang, R. Guan, K. He, J. Jiang, G. Baumann, R. A. Black, M. S. Wolfe, and S. J. Frank (2005)
J. Biol. Chem. 280, 19331-19342
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882