Transcription of beta-casein (CSN2) PathwayStep5382 PathwayStep5389 PathwayStep5388 PathwayStep5387 PathwayStep5386 PathwayStep5385 PathwayStep5384 PathwayStep5383 PathwayStep5391 PathwayStep5390 PathwayStep5393 PathwayStep5392 PathwayStep5395 PathwayStep5394 PathwayStep5396 PathwayStep5411 ERBB4s80 binds STAT5A ERBB4s80:STAT5A complex translocates to the nucleus ERBB4s80 forms a complex with estrogen receptor ESR1 Transcription of NR3C3 and CXCL12 Translocation of cytosolic ERBB4s80 to mitochondrial matrix Cleavage of P-ERBB4jmA isoforms by ADAM17 Cleavage of ERBB4m80 by gamma-scretase complex Translocation of ERBB4s80:YAP1 complex to the nucleus WWOX binds ERBB4s80 ERBB4s80 binds YAP1 ERBB4:TAB2:NCOR1 complex translocates to the nucleus Transcription of GFAP and S100B Translocation of ERBB4s80 to the nucleus ERBB4s80 binds TAB2:NCOR1 complex Nuclear signaling by ERBB4 Authored: Orlic-Milacic, M, 2011-11-04 Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). <br><br>The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006). Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431251985 Reactome, http://www.reactome.org ReactomeREACT_116022 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 Prolactin receptor signaling