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 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.

[1]  N. Navin,et al.  WW Domain-containing Protein YAP Associates with ErbB-4 and Acts as a Co-transcriptional Activator for the Carboxyl-terminal Fragment of ErbB-4 That Translocates to the Nucleus* , 2003, Journal of Biological Chemistry.

[2]  N. Kudo,et al.  Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. Gassmann,et al.  ErbB4 Signaling During Breast and Neural Development: Novel Genetic Models Reveal Unique ErbB4 Activities , 2003, Cell cycle.

[4]  T. van Raaij,et al.  The cellular response to neuregulins is governed by complex interactions of the erbB receptor family , 1995, Molecular and cellular biology.

[5]  Yan Tang,et al.  Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of Bcl-2 by anti-oestrogens , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  L. Kinnunen,et al.  Arginine/Lysine-rich Structural Element Is Involved in Interferon-induced Nuclear Import of STATs* , 2001, The Journal of Biological Chemistry.

[7]  L. Mei,et al.  Presenilin-dependent γ-Secretase-like Intramembrane Cleavage of ErbB4* , 2002, The Journal of Biological Chemistry.

[8]  B. Barre,et al.  Opposite Regulation of Myc and p21 waf1 Transcription by STAT3 Proteins* , 2003, The Journal of Biological Chemistry.

[9]  C. Carter-Su,et al.  A Functional DNA Binding Domain Is Required for Growth Hormone-induced Nuclear Accumulation of Stat5B* , 1999, The Journal of Biological Chemistry.

[10]  K. Makino,et al.  Nuclear localization of EGF receptor and its potential new role as a transcription factor , 2001, Nature Cell Biology.

[11]  D. Stern,et al.  Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Barnes,et al.  Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. , 2000, Cancer research.

[13]  U. Vinkemeier,et al.  Constitutive and IFN-gamma-induced nuclear import of STAT1 proceed through independent pathways. , 2002, The EMBO journal.

[14]  I. Lödige,et al.  Constitutive and IFN‐γ‐induced nuclear import of STAT1 proceed through independent pathways , 2002 .

[15]  J. Buxbaum,et al.  Tumor Necrosis Factor-α-converting Enzyme Is Required for Cleavage of erbB4/HER4* , 2000, The Journal of Biological Chemistry.

[16]  Xin-Yuan Fu,et al.  Erbb4 Signaling in the Mammary Gland Is Required for Lobuloalveolar Development and Stat5 Activation during Lactation , 1999, The Journal of cell biology.

[17]  T. Golde,et al.  γ-Secretase Cleavage and Nuclear Localization of ErbB-4 Receptor Tyrosine Kinase , 2001, Science.

[18]  S. Geley,et al.  A distal enhancer region in the human beta-casein gene mediates the response to prolactin and glucocorticoid hormones. , 1998, Gene.

[19]  Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5 , 2003, Development.

[20]  David L. Spector,et al.  Nuclear speckles: a model for nuclear organelles , 2003, Nature Reviews Molecular Cell Biology.

[21]  Andreas Marg,et al.  DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1. , 2003, Genes & development.

[22]  M. Klagsbrun,et al.  A Novel Juxtamembrane Domain Isoform of HER4/ErbB4 , 1997, The Journal of Biological Chemistry.

[23]  Raphael Kopan,et al.  Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain , 1998, Nature.

[24]  Rüdiger Klein,et al.  Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor , 1995, Nature.

[25]  G. Plowman,et al.  Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Buxbaum,et al.  Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4. , 2000, The Journal of biological chemistry.

[27]  L. Caskey,et al.  HER4 Mediates Ligand-Dependent Antiproliferative and Differentiation Responses in Human Breast Cancer Cells , 2001, Molecular and Cellular Biology.

[28]  G. Carpenter,et al.  Role of the ErbB-4 Carboxyl Terminus in γ-Secretase Cleavage* , 2003, The Journal of Biological Chemistry.

[29]  G. Plowman,et al.  Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. , 1993, Proceedings of the National Academy of Sciences of the United States of America.