Nuclear signaling by ERBB4

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R-HSA-1251985
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Pathway
Species
Homo sapiens
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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). ERBB4s80 may inhibit transcription of telomerase reverse transcriptase (TERT) by increasing methylation of the TERT gene promoter through an unknown mechanism (Ishibashi et al. 2012).

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).

Literature References
PubMed ID Title Journal Year
12869563 Ectodomain cleavage of ErbB-4: characterization of the cleavage site and m80 fragment

Cheng, QC, Tikhomirov, O, Zhou, W, Carpenter, G

J Biol Chem 2003
15534001 The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone

Williams, CC, Allison, JG, Vidal, GA, Burow, ME, Beckman, BS, Marrero, L, Jones, FE

J Cell Biol 2004
16912174 Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells

Zhu, Y, Sullivan, LL, Nair, SS, Williams, CC, Pandey, AK, Marrero, L, Vadlamudi, RK, Jones, FE

Cancer Res 2006
10744726 Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4

Rio, C, Buxbaum, JD, Peschon, JJ, Corfas, G

J Biol Chem 2000
11679632 gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase

Ni, CY, Murphy, MP, Golde, TE, Carpenter, G

Science 2001
16778220 The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells

Naresh, A, Long, W, Vidal, GA, Wimley, WC, Marrero, L, Sartor, CI, Tovey, S, Cooke, TG, Bartlett, JM, Jones, FE

Cancer Res 2006
17018285 Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain

Sardi, SP, Murtie, J, Koirala, S, Patten, BA, Corfas, G

Cell 2006
16061658 WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function

Aqeilan, RI, Donati, V, Palamarchuk, A, Trapasso, F, Kaou, M, Pekarsky, Y, Sudol, M, Croce, CM

Cancer Res 2005
15023535 Ligand-regulated association of ErbB-4 to the transcriptional co-activator YAP65 controls transcription at the nuclear level

Omerovic, J, Puggioni, EM, Napoletano, S, Visco, V, Fraioli, R, Frati, L, Gulino, A, Alimandi, M

Exp Cell Res 2004
23230144 Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-Src

Ishibashi, K, Fukumoto, Y, Hasegawa, H, Abe, K, Kubota, S, Aoyama, K, Kubota, S, Nakayama, Y, Yamaguchi, N

J. Cell. Sci. 2013
12807903 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

Komuro, A, Nagai, M, Navin, NE, Sudol, M

J Biol Chem 2003
18653779 Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation

Muraoka-Cook, RS, Sandahl, MA, Hunter, D, Miraglia, L, Earp HS, 3rd

Mol Endocrinol 2008
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