Editors' ChoiceGene Expression

ErbB4 Escorts STAT5 to the Nucleus

Science's STKE  16 Nov 2004:
Vol. 2004, Issue 259, pp. tw410
DOI: 10.1126/stke.2592004tw410

ErbB4 is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. However, ErbB4 appears to have a signaling mechanism that involves cleavage of the protein at the membrane to release intracellular (4ICD) and extracellular fragments. Williams et al. report that the 4ICD fragment contains functional nuclear localization and nuclear export signals and appears to serve as a nuclear chaperone for STAT5 (a transcription factor of the signal transducer and activator of transcription family). Heregulin (Hrg), the ligand for ErbB4, stimulates the lactating breast to produce milk proteins through a pathway involving STAT5. Williams et al. showed that in cells transfected with wild-type tagged ErbB4 or ErbB4 with a mutation in the nuclear localization signal (NLS) in the 4ICD, Hrg only stimulated STAT5 nuclear accumulation in cells expressing the wild-type ErbB4. Furthermore, Hrg stimulation of reporter gene activity of the STAT5-regulated β-casein gene also required a functional NLS in ErbB4. In vivo, the interaction between STAT5 and 4ICD was detected at the ß-casein promoter by chromatin immunoprecipitation experiments in T47 breast cancer cells in response to Hrg treatment. Thus, ErbB4 appears to use a novel signaling pathway involving juxtamembrane cleavage, which produces a nuclear chaperone for STAT5 in lactating breast.

C. C. Williams, J. G. Allison, G. A. Vidal, M. E. Burrow, B. S. Beckman, L. Marrero, F. E. Jones, The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. J. Cell. Biol. 167, 469-478 (2004). [Abstract] [Full Text]