A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors.
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ABSTRACT:
SUBMITTER: El-Gamal MI
PROVIDER: S-EPMC8659013 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:HER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor tyrosine kinases that is essential for normal development of the heart, nervous system, and mammary gland. We report here crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an asymmetric dimer conformation essentially identical to that observed to be important for activation of the EGF receptor/ErbB1 kinase. Mutagenesis studies of intact ErbB4 in Ba/F3 cells confirm the importance of this asymmetric dimer for activation of intact ErbB4. Lapatinib binds to an inactive form of the ErbB4 kinase in a mode equivalent to its interaction with the EGF receptor. All ErbB4 residues contacted by lapatinib are conserved in the EGF receptor and HER2/ErbB2, which lapatinib also targets. These results demonstrate that key elements of kinase activation and inhibition are conserved among ErbB family members.
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Project description:In the ErbB/HER family of receptor tyrosine kinases, the deregulation of the EGFR/ErbB1/HER1, HER2/ErbB2, and HER3/ErbB3 kinases is associated with several cancers, while the HER4/ErbB4 kinase has been shown to play an anti-carcinogenic role in certain tumors. We present molecular and network models of HER4/ErbB4 activation and signaling in order to elucidate molecular mechanisms of activation and rationalize the effects of the clinically identified HER4 somatic mutants. Our molecular-scale simulations identify the important role played by the interactions within the juxtamembrane region during the activation process. Our results also support the hypothesis that the HER4 mutants may heterodimerize but not activate, resulting in blockage of the HER4-STAT5 differentiation pathway, in favor of the proliferative PI3K/AKT pathway. Translating our molecular simulation results into a cellular pathway model of wild type versus mutant HER4 signaling, we are able to recapitulate the major features of the PI3K/AKT and JAK/STAT activation downstream of HER4. Our model predicts that the signaling downstream of the wild type HER4 is enriched for the JAK-STAT pathway, whereas downstream of the mutant HER4 is enriched for the PI3K/AKT pathway. HER4 mutations may hence constitute a cellular shift from a program of differentiation to that of proliferation.
| S-EPMC3934553 | biostudies-literature
Project description: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 beta-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the beta-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin beta 1 (HRG)-stimulated cells and both proteins bind to the endogenous beta-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.
| S-EPMC2172499 | biostudies-literature
Project description:Differentiation of mammary epithelium in vivo requires signaling through prolactin and ErbB4/HER4-dependent mechanisms. Although stimulation of either the prolactin receptor or ErbB4/HER4 results in activation of the transcription factor signal transducer and activator of transcription 5A (STAT5A) and induction of lactogenic differentiation, how these pathways intersect is unknown. We show herein that prolactin signaling in breast cells cooperates with and is substantially enhanced by the receptor tyrosine kinase ErbB4/HER4. Prolactin and the ErbB4/HER4 ligand heparin-binding epidermal growth factor each induced STAT5A tyrosine phosphorylation and nuclear translocation; each pathway required the intracellular tyrosine kinase Janus kinase 2 (JAK2). We found that full prolactin-mediated STAT5A activation and binding to the endogenous beta-casein promoter required ErbB4/HER4 but did not require ErbB1/epidermal growth factor receptor. For example, prolactin-induced STAT5A activity was markedly diminished in cells overexpressing kinase inactive HER4, in cells transfected with small interfering RNAs to specifically knock down endogenous ErbB4/HER4 expression and in cells treated with a small molecule inhibitor that targets ErbB4 kinase. Interestingly, prolactin caused ErbB4/HER4 tyrosine phosphorylation in a JAK2 kinase-dependent manner. Finally, prolactin receptor, ErbB4/HER4, and JAK2 were coimmunoprecipitated from prolactin-treated but not untreated cells. These results suggest that prolactin signaling engages the ErbB4 pathway via JAK2 and that ErbB4 provides an important component of STAT5A-dependent lactogenic differentiation; this pathway integration may help explain the similar deficit in mammary development observed in gene-targeted mice deficient in prolactin receptor, JAK2, ErbB4, or STAT5A.
| S-EPMC2582536 | biostudies-literature
Project description:Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial. We demonstrate that genetic ablation of ERBB4, but not ERBB1-3, led to apoptosis in lapatinib-resistant cells, suggesting that the efficacy of pan-ERBB inhibitors was, at least in part, mediated by the inhibition of ERBB4. Moreover, ERBB4 was upregulated at the protein level in ERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment. Knockdown of ERBB4 caused a decrease in AKT phosphorylation in resistant cells but not in sensitive cells, suggesting that ERBB4 activated the PI3K/AKT pathway in lapatinib-resistant cells. Importantly, ERBB4 knockdown triggered apoptosis not only in lapatinib-resistant cells but also in trastuzumab-resistant cells. Our results suggest that although ERBB4 is dispensable for naïve ERBB2+ breast cancer cells, it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors, lapatinib and trastuzumab.
| S-EPMC4614407 | biostudies-literature
Project description:Tyrosine kinase receptors promote the growth and differentiation of normal breast and malignant human breast cancer cells, known as ERBB receptors. Various ERBB receptors are EGFR/ErbB1 and ErbB2/neu, which get over expressed in different solid tumors that activate upon binding of ligand to the extra cellular domain of these receptors. Of note, the epidermal growth factor receptor (EGFR) is a prime contributor to cancer through the involvement of four receptor tyrosine kinases (RTKs), namely, HER1, HER2, HER3, and HER4. Among them, HER2 and HER4 are majorly associated with breast cancer. Non-peptide quinazoline compounds homologous of the adenosine triphosphate (ATP) are competitively inhibited to RTKs to prevent cancer growth and metastasis. Various small drug molecule that targets the RTKs having the same scaffold, includes Lapatinib, Tivozanib, Erlotinib, Gefitinib, Crizotinib, and Ceritinib. The present study aims to investigate the comparative potential of structurally similar TKIs against HER2 and HER4 receptor receptors-silico molecular docking using FlexX software (LeadIT 2.3.2). Each docked complex's interaction profile was performed using BIOVIA Discovery Studio Visualizer 4.0. Molecular docking analysis was performed in order to get deeper insights into the interaction and binding pattern of the ligands with HER2 and HER4 receptors. The docking results revealed the Lapatinib compound acquired the relatively highest binding score of -32.36 kcal/mol and -35.76 kcal/mol with HER2 and HER4 proteins, respectively, concerning other compounds. Lapatinib is identified as a potential inhibitor for both the RTKs. Our study thus suggests the probable direction that could be further explored in inhibiting EGFR protein harboring breast cancer.
| S-EPMC10465783 | biostudies-literature
Project description:Experimental and clinical data support a growth inhibitory role for HER4 in breast cancer. Clinically HER4 expression is extinguished during breast tumorigenesis supporting a tumor suppressor function for HER4, however, a molecular mechanism to explain the selective loss of HER4 expression has remained elusive. Epigenetic mechanisms, for example, aberrant gene promoter hypermethylation, have been shown to ablate tumor suppressor gene expression in breast carcinomas. We identified a CpG island within the HER4 promoter and show by pyrosequencing of bisulfite-treated DNA an inverse correlation between HER4 expression and the extent of promoter methylation. Treatment of the HER4-negative BT20 cell line with the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC)-enhanced HER4 expression, confirming a role for DNA methylation in suppressed HER4 expression. DAC treatment to reactive HER4 expression in combination with the HER4 ligand heregulin-?1 (HRG) resulted in apoptosis of BT20 cells providing a novel therapeutic strategy for triple-negative tumors. The BT20 cells were rescued from apoptosis when preincubated with HER4 small interfering RNA, thereby confirming a role for HER4 in DAC/HRG-induced apoptosis. We verified HER4 promoter methylation in primary breast carcinomas and detected a significant increase in HER4 promoter methylation in HER4-negative breast tumors (P<0.001). Furthermore, increased levels of HER4 promoter methylation were significantly associated with worse patient prognosis (P=0.0234). Taken together, our data support a tumor suppressor function for HER4, which is epigenetically suppressed in breast tumors through promoter hypermethylation.
| S-EPMC3007096 | biostudies-literature
Project description:Anti-epidermal growth factor receptor (EGFR)-targeted therapy has been intensely researched in the last years, motivated by the favorable results obtained with monoclonal antibodies in HER2-enriched breast cancer (BC) patients. Most researched alternatives of anti-EGFR agents were tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. However, excluding monoclonal antibodies trastuzumab and pertuzumab, the remaining anti-EGFR molecules have exhibited disappointing results, due to the lack of specificity and frequent adverse side effects. TKIs have several advantages, including reduced cardiotoxicity, oral administration and favorable penetration of blood-brain barrier for brain metastatic BC. Lapatinib and neratinib and recently pyrotinib (approved only in China) are the only TKIs from dozens of molecules researched over the years that were approved to be used in clinical practice with limited indications, in a subset of BC patients, single or in combination with other chemotherapy or hormonal therapeutic agents. Improved identification of BC subtypes and improved characterization of aggressive forms (triple negative BC or inflammatory BC) should lead to advancements in shaping of targeted agents to improve the outcome of patients.
| S-EPMC8713180 | biostudies-literature
Project description:INTRODUCTION: We have previously linked HER4 expression with increased survival in breast cancer. However, other reports have associated HER4 with adverse prognostic significance. One possible explanation for the conflicting reports may be that these results are antibody dependent. The HER4 protein is enzymatically cleaved, which may alter the function of its intracellular domain (ICD). We have therefore compared the staining patterns of antibodies against its intracellular and extracellular domains using tissue microarray technology. METHODS: Immunohistochemistry was performed and evaluated on tumours from 402 tamoxifen treated oestrogen receptor positive patients. The HFR1 antibody recognises the ICD of HER4 and thus recognises both the intact receptor and the cleaved ICD. The H4.77.16 clone recognises an extracellular domain of HER4 and thus detects the full length receptor only. RESULTS: Both antibodies demonstrated nuclear, cytoplasmic and membranous staining. Concordance between the membrane staining patterns was high (88.44%, kappa 0.426). The HFR1 antibody, however, demonstrated generally higher levels of cytoplasmic staining (concordance 74.77%, kappa 0.351). The antibodies demonstrated very different patterns of nuclear staining. Over 60% of patients stained with the H4.77.16 had no nuclear staining whereas the vast majority showed staining with the HFR1 antibody (concordance 40.12%, kappa 0.051). Neither antibody demonstrated relationships between membranous or cytoplasmic HER4 staining and survival, although associations were seen with known poor prognostic markers. Cases with H4.77.16-determined nuclear staining had significantly poorer survival outcomes. CONCLUSION: The difference in antigen site may explain the different staining patterns we have seen with respect to location; with each antibody appearing to select for distinct compartments. Thus, HFR1 may select for cytoplasmic and nuclear HER4 ICD, whilst H4.77.16 selects for membranous HER4 and/or HER4 being recycled in cytoplasm or nucleus. This ability to distinguish between site and function of HER4 and its fragments is particularly important, with recent evidence highlighting the different functions of nuclear and mitochondrial HER4.
| S-EPMC1557726 | biostudies-literature
Project description:Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.
| S-EPMC5687690 | biostudies-literature