ERBB4

Official Full Name

erb-b2 receptor tyrosine kinase 4

Organism

Homo sapiens

GeneID

2066

Background

This gene is a member of the Tyr protein kinase family and the epidermal growth factor receptor subfamily. It encodes a single-pass type I membrane protein with multiple cysteine rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphotidylinositol-3 kinase binding site and a PDZ domain binding motif. The protein binds to and is activated by neuregulins and other factors and induces a variety of cellular responses including mitogenesis and differentiation. Multiple proteolytic events allow for the release of a cytoplasmic fragment and an extracellular fragment. Mutations in this gene have been associated with cancer. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

Synonyms

HER4; ALS19; p180erbB4;

Bio Chemical Class

mRNA target

Protein Sequence

MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVMGNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIFLNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVSTNGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSGPKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVDSSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCTKINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNLVTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFSTINQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYDGEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGANSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGGLFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHLVRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQSDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMIDADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAEEYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVPYRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERSPRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAEDEYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQEYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV

Open

Approved Drug

1 +

Clinical Trial Drug

4 +

Discontinued Drug

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Detailed Information

The ERBB4 gene, also known as Erb-B2 Receptor Tyrosine Kinase 4 or HER4, is a member of the Epidermal Growth Factor Receptor (EGFR) subfamily of receptor tyrosine kinases (RTKs). Like other members of this family, ERBB4 is essential for cell signaling, especially in the control of several biological processes including survival, differentiation, and cell proliferation. It codes for a transmembrane protein having several cysteine-rich domains, a transmembrane domain, a tyrosine kinase domain, a phosphoinositide-3-kinase (PI3K) binding site, and a PDZ domain binding motif.

Neuregulins (NRGs) attach to the receptor and set off many downstream signaling cascades, hence activating ERBB4. Cellular responses including mitogenesis, differentiation, and migration depend on these pathways. Crucially, mutations or changes in ERBB4 have been linked to some malignancies; while their exact therapeutic consequences are yet under investigation.

Figure 1 illustrates the intracellular signaling pathways of ErbB4 receptors, highlighting their activation of the ERK and AKT pathways, as well as the cleavage of the JMa isoform, leading to the generation of ErbB4-ICD, which then dimerizes with STAT5A for nuclear translocation. Figure 1. Intracellular signaling pathways of ErbB4 receptors. (Segers VFM, et al., 2020)

ERBB4 in Cancer Pathophysiology

Melanoma, lung adenocarcinoma, and medulloblastoma are among the various cancer forms for which ERBB4 has been linked in pathogenesis. ERBB4's function in cancer is very different from that of other ErbB family members as, depending on the circumstances, it seems to have both tumor-suppressing and tumor-promoting qualities. Many malignancies have downregulated the expression of the gene, which might help to explain the loss of its tumor-suppressive action.

ERBB4 mutations in lung adenocarcinoma and melanoma can cause changes in signaling pathways, possibly promoting cancer development. ERBB4, in contrast to other ErbB family receptors, is not usually linked to aggressive tumor behavior nevertheless. ERBB4 expression is commonly lowered in more advanced stages of cancer, which implies that its absence may support the growth of tumors in numerous forms of the disease. Results from The Cancer Genome Atlas further support this; reduction of ERBB4 gene copy counts links with poor prognosis in malignancies including bladder carcinoma, esophageal, and lung.

Notwithstanding these findings, there is still much disagreement over exactly ERBB4's role in cancer. While in cancer cells its absence may help tumor growth and metastases, some research proposes that ERBB4 could operate as a tumor suppressor, limiting proliferation and promoting differentiation in normal tissues.

ERBB4 in Development and Physiology

In addition to its role in cancer, ERBB4 plays a crucial role in normal development and tissue homeostasis, particularly in the heart, nervous system, and mammary glands. During embryonic development, ERBB4 is essential for normal cardiac differentiation and neural crest migration. Mice lacking ERBB4 expression die early in embryonic development due to heart defects, underscoring the importance of this gene in early tissue development.

In the mammary gland, ERBB4 promotes the differentiation of epithelial cells during pregnancy and lactation but does not play a major role in cell proliferation. This contrasts with other ErbB receptors, such as EGFR and HER2, which are associated with epithelial cell proliferation. Loss of ERBB4 in transgenic mice has been shown to impair lactation and the differentiation of mammary tissue, further highlighting its role in regulating tissue-specific responses.

Additionally, ERBB4 signaling is vital in the central nervous system, where it governs neuronal migration and axon guidance. Neuregulin-1, a ligand for ERBB4, is highly expressed in the brain, and disruptions in ERBB4 signaling have been linked to neurodevelopmental disorders such as schizophrenia.

ERBB4's involvement in the cardiovascular system is another critical aspect of its physiological role. The NRG-1/ERBB4 axis plays an important role in cardiac homeostasis, and its activation has been shown to protect against heart failure. Ongoing clinical trials are investigating the use of NRG-1 as a potential treatment for heart failure, based on its ability to activate ERBB4 and promote cardiomyocyte proliferation and survival.

ERBB4 in Immune Response and Fibrosis

ERBB4 activation has also been implicated in immune regulation. Recent studies have shown that activation of ERBB4 on macrophages can suppress the release of inflammatory cytokines, suggesting a role for this receptor in modulating immune responses. Furthermore, ERBB4 signaling has anti-fibrotic effects in various tissues, including the heart, lungs, and kidneys. This suggests that ERBB4 could be targeted for therapeutic interventions in fibrotic diseases, where excessive tissue scarring occurs.

References:

Segers VFM, Dugaucquier L, et al. The role of ErbB4 in cancer. Cell Oncol (Dordr). 2020 Jun;43(3):335-352.
Pitcher JL, Alexander N, et al. ErbB4 in the brain: Focus on high-grade glioma. Front Oncol. 2022 Aug 31;12:983514.

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