Disease relevance of ERBB4

• 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 beta-casein promoter activity [1].
• Significantly, ERBB4-CA potentiated the proapoptotic function of ERBB4 in each breast, prostate and ovarian cancer cell line tested [2].
• We detected the ERBB4 somatic mutations in 3 of 180 gastric carcinomas (1.7%), 3 of 104 colorectal carcinomas (2.9%), 5 of 217 nonsmall cell lung cancers (2.3%) and 1 of 94 breast carcinomas (1.1%) [3].
• CONCLUSION: We hypothesise that: (i) ERBB4 is important for differentiation in NU; (ii) ERBB2 is up-regulated with carcinogenesis in the urinary bladder but does not discriminate between bladder cancer with or without metastases; (iii) EGFR may be a marker of indolent disease [4].
• In contrast, the lack of HER-4 expression might increase the metastatic capacity of pancreatic cancer cells [5].

High impact information on ERBB4

• Furthermore, heregulin fails to induce phosphorylation of HER2 in the absence of HER4 [6].
• Heregulin induces tyrosine phosphorylation of HER4/p180erbB4 [6].
• These findings suggest that activation of the HER4 receptor is involved in signal transduction by heregulin [6].
• We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells [7].
• The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone [1].

Chemical compound and disease context of ERBB4

• The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells [8].
• In this report we describe the purification to homogeneity of a 45-kDa protein (p45) that induces the differentiation of MDA-MB-453 human breast cancer cells and stimulates the tyrosine phosphorylation of p180erbB4, the HER4-encoded protein [9].
• Using a cell proliferation assay and a small interfering RNA approach, we show that ERBB4 expression is required for the growth-promoting action of estrogen in the T47D breast cancer cell line [10].
• The HER4 receptor protein is strongly expressed by normal prostate luminal cells, but not prostate cancer [11].
• Here we demonstrate that retinoid acid- mediated growth inhibition is accompanied with reduced expression of c-erbB-4/HER4 in T47D breast cancer cells as determined by FACS, Western, and RT-PCR [12].

Biological context of ERBB4

• Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression [8].
• Our recent data suggests that regulation of gene expression by the ERBB4 nuclear protein and the proapoptotic activity of ERBB4 involves the gamma-secretase release of 4ICD [13].
• The 12 ERBB4 mutations consisted of 1 in-frame duplication mutation and 8 missense mutations in the exons, and 3 mutations in the introns [3].
• In contrast, the phenotypes of transgenic mice expressing dominant negative ERBB2 and ERBB4 proteins suggest that these receptors differentially act to promote or maintain alveolar differentiation [14].
• On the other hand, HB-EGF is not a mitogen for cells expressing HER4, in contrast to its ability to stimulate both chemotaxis and proliferation in cells expressing HER1 [15].

Anatomical context of ERBB4

• 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 [1].
• Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5 [16].
• We also demonstrate that 4ICD failed to accumulate within mitochondria of ERBB4-V673I transfected cells and the potent proapoptotic activity of ERBB4 was completely abolished in cells expressing ERBB4-V673I [13].
• Furthermore, this heparin-binding protein induces phenotypic differentiation, and tyrosine phosphorylation, of a human mammary tumor cell line that overexpresses both HER4 and HER2 [17].
• However, their expressions (except for HER-4) were significantly associated with the presence of lymph node metastasis, and all of them were significantly associated with distant metastasis [18].

Associations of ERBB4 with chemical compounds

• Hydrophobic interaction, ion-exchange, heparin, and size exclusion chromatographies were used to purify this p180erbB4 activator to homogeneity [9].
• Estrogen induces nuclear translocation of the proteolytic processed ERBB4 intracellular domain (4ICD) and nuclear translocation of 4ICD requires functional ligand-bound ER [10].
• We also determined the relationship of Neu, phosphorylated Neu (and epidermal growth factor receptor), and phosphotyrosine to the expression of Neu-related receptors (epidermal growth factor receptor, HER-3, and HER-4) and to prognostic factors (estrogen and progesterone receptor) [19].
• RESULTS: HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060) [20].
• Function-blocking antibodies against EGF family members reduced basal cell motility and antibody inhibition of either HER1 or HER4 ligation prevented HB-EGF-induced integrin switching [21].
• These results indicate that surface HER4 tyrosine phosphorylation and ligand-dependent release of s80HER4 are necessary, and s80HER4 signaling is sufficient for HER4-dependent growth inhibition [22].

Physical interactions of ERBB4

• This ligand phosphorylates the HER-2/neu receptor and binds directly to HER-4 and HER-3 [23].

Co-localisations of ERBB4

• HB-EGF colocalized with HER-1 and HER-4 in HPMCs and induced their adhesion to collagen type I, expression of beta 1 integrins, and migration [24].

Regulatory relationships of ERBB4

• Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the beta-casein promoter [2].
• Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities [13].
• By reverse transcription polymerase chain reaction and Western blotting, we found that the breast cells also express HER3 and that the ovarian line co-expresses the HER4 message [25].
• In contrast, the ovarian cells expressing high levels of HER2 and low levels of HER4 or CHO-K1 and 293-EBNA cells expressing HER2 alone were not responsive to heregulin [25].
• CONCLUSIONS: HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling [26].

Other interactions of ERBB4

• This report describes the isolation and recombinant expression of a cDNA clone encoding HER4, the fourth member of the human epidermal growth factor receptor (EGFR) family [17].
• We found a positive correlation between ERBB3 and ERBB4 mRNA levels, and a negative correlation between the expression of these 2 latter genes and that of ERBB1 [27].
• In the normal breast, ERBB4 regulates epithelial differentiation and functions as a nuclear chaperone for signal transducer and activator of transcription (STAT) 5A, thereby stimulating milk-gene expression [2].
• Here, we performed mutational analysis of the ERBB4 kinase domain by polymerase chain reaction-single-strand conformation polymorphism assay in 595 cancer tissues from stomach, lung, colon and breast [3].
• Since limited information exists concerning the expression of other parts of the EGF system, we examined the expression of the receptors HER3 and HER4 and their activating ligands, the heregulins (HRGs), in bladder cancer patients [28].

Analytical, diagnostic and therapeutic context of ERBB4

• Since about 20% of human breast cancers overexpress HER-2 and some of breast cancer cell lines overexpress both HER-2 and HER-4, cell-specific targeting of retroviral vectors may provide a different approach for in vivo gene therapy of this type of breast cancer [29].
• To investigate whether coexpression results in receptor heterodimerization, we have also performed immunoprecipitation analysis of protein extracts from primary tumors, and we demonstrate various patterns of receptor interaction including between HER2 and HER4 [30].
• Potentially, HER4 expression may identify women who could avoid radiotherapy after breast-conserving surgery for DCIS [31].
• HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue [32].
• In the current study, we employed an RT-PCR and sequencing strategy to determine the pattern of ERBB4 JM isoform expression in a large (n = 78) series of pediatric medulloblastomas [33].
• HER4 has been found to be the most frequently mutated PTK gene in melanoma  .

References