HER3

Official Full Name

erb-b2 receptor tyrosine kinase 3

Organism

Homo sapiens

GeneID

2065

Background

This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

Synonyms

HER3; FERLK; LCCS2; VSCN1; ErbB-3; c-erbB3; erbB3-S; MDA-BF-1; c-erbB-3; p180-ErbB3; p45-sErbB3; p85-sErbB3;

Bio Chemical Class

mRNA target

Protein Sequence

MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVMGNLEIVLTGHNADLSFLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAIFVMLNYNTNSSHALRQLRLTQLTEILSGGVYIEKNDKLCHMDTIDWRDIVRDRDAEIVVKDNGRSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQCCHDECAGGCSGPQDTDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTSCVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGNLDFLITGLNGDPWHKIPALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGGRSLYNRGFSLLIMKNLNVTSLGFRSLKEISAGRIYISANRQLCYHHSLNWTKVLRGPTEERLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSRGGVCVTHCNFLNGEPREFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPIYKYPDVQNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLGGTFLYWRGRRIQNKRAMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVFGTVHKGVWIPEGESIKIPVCIKVIEDKSGRQSFQAVTDHMLAIGSLDHAHIVRLLGLCPGSSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYLEEHGMVHRNLAARNVLLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVTVWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKELANEFTRMARDPPRYLVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEEDNLATTTLGSALSLPVGTLNRPRGSQSLLSPSSGYMPMNQGNLGESCQESAVSGSSERCPRPVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPRPRGDSAYHSQRHSLLTPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYMNRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDYEYMNRQRDGGGPGGDYAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATDSAFDNPDYWHSRLFPKANAQRT

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

22 +

Discontinued Drug

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Detailed Information

The ERBB3 gene, part of the epidermal growth factor receptor family, is located on chromosome 12q13 and encodes the ERBB3 protein, also known as HER3. During embryonic development, ERBB3 is expressed extensively in tissues such as the skin, bone, muscles, nervous system, heart, lungs, and intestinal epithelium. As individuals mature, this expression continues to be important in the gastrointestinal tract, reproductive system, urinary tract, and skin, underscoring its role in both development and physiological maintenance.

Protein Structure and Mechanisms

ERBB3 is constructed with an extracellular ligand-binding domain, a transmembrane segment, and an intracellular domain. The extracellular domain is crucial for ligand interaction, while the intracellular domain contains regions necessary for protein-protein interaction and signal transduction, though it is unique in the ErbB family for lacking intrinsic tyrosine kinase activity. Instead, ERBB3 relies on heterodimerizing with ERBB2, allowing the complex to activate multiple downstream signaling pathways that influence cell survival and proliferation.

Figure 1 illustrates the structural changes and activation process of HER3 upon ligand binding and heterodimer formation. Figure 1. Schematic diagram of HER3 structural changes and activation. (Gandullo-Sánchez L, et al., 2022)

Functional Dynamics and Pathway Involvement

Like with heregulin and neuregulins, ligand binding predominantly turns on ERBB3. This alters the structure to facilitate two ERBBs joining together. This dimerization is a major activator of the PI3K/Akt pathway—important for cell growth and survival—when ERBB3 or ERBB2 levels are too high. It also contributes to cancer signaling.

ERBB3 helps the brain grow and develop through neural crest derivatives such as Schwann cells differentiating when the body's regular processes occur. It also enables the heart to develop and mature, particularly concerning producing the atrioventricular valves. By altering pathways like MAPK and PI3K, ERBB3 helps regulate cell growth, motility, and death. This indicates that it participates in significant biological activities outside of cancer.

ERBB3 in Cancer: From Oncogenesis to Therapeutic Resistance

Common in many cancers, including lung, breast, ovarian, and colon cancer, ERBB3 rise is Strong signaling complexes produced by ERBB2 interaction that enable cells to proliferate and survive, hence promoting cancer spread and growth. Curiously, ERBB3 lacks self-phosphorylation capacity but operates via contacts enabling transphosphorylation. These provide powerful signals encouraging cancer development.

ERBB3 has been connected to cancer cells failing to react to several kinds of therapy. Specifically, in breast tumors that are positive for HER2, ERBB3 activates alternative survival pathways, primarily PI3K/Akt, allowing the malignancy to evade therapies aimed at HER2. Similar mechanisms are seen in lung cancer, where ERBB3 involvement reduces the efficacy of EGFR medications. This emphasizes how crucial the protein is in the capacity of cancer to alter.

Therapeutic Strategies Targeting ERBB3

Different techniques are used to alter how ERBB3 functions as it is significant in cancer biology; mostly monoclonal antibodies and bispecific antibodies. Monoclonal antibodies aimed at ERBB3 may prevent dimerization, hence preventing cancer signaling by preventing ligand binding. Most of them, meanwhile, have not performed very well on their own, which is why scientists are investigating combination therapies or novel forms including bispecific antibodies, which simultaneously target ERBB3 and other EGFR family members.

A novel approach to target ERBB3 is via ADCs, which are mixes of antibodies and medications. These conjugates deliver the medications straight to cancer cells by linking pharmaceuticals that kill cells to antibodies that target ERBB3, hence minimizing adverse effects and circumventing the issues resulting from ERBB3 being kinase-dead. Currently undergoing clinical trials, these therapies show early promise in reducing tumors and improving patient outcomes.

Future Directions in ERBB3-Targeted Therapy

Continuing to develop ERBB3-targeting strategies could provide very beneficial drugs for cancer treatment. New therapies may be developed to make them more focused and combat cancer resistance to them as more is known about how ERBB3 interacts with other molecules and how it delivers signals. Combining ERBB3-targeted medications, tailored medicine, and immunotherapy could provide improved approaches to managing resistant cancer types, which would finally improve patient outcomes.

All things considered, ERBB3 is a complicated and significant protein that enables cell communication and supports cancer development. Learning more about how it interacts with other receptors might help researchers create novel therapies that could alter the treatment of cancer and enable more people to live. ERBB3 will remain a subject of research aimed at addressing some of the most challenging current cancer issues as we know more.

References:

Papa F, Grinda T, Rassy E, et al. Long road towards effective HER3 targeting in breast cancer. Cancer Treat Rev. 2024;129:102786.
Gandullo-Sánchez L, Ocaña A, Pandiella A. HER3 in cancer: from the bench to the bedside. J Exp Clin Cancer Res. 2022;41(1):310.

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