ERBB2 - erb-b2 receptor tyrosine kinase 2 |Elisa - Clia - Antibody - Protein

Background

ERBB2, also known as HER2 (human epidermal growth factor receptor 2), is a receptor tyrosine kinase that is part of the ERBB receptor family. This family consists of four closely related receptors: EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These receptors play crucial roles in cellular signaling pathways regulating cell growth, differentiation, survival, and apoptosis. ERBB2 is particularly significant due to its role in breast cancer and other cancers, where its overexpression or gene amplification is associated with aggressive tumor behavior and poor prognosis. ERBB2 lacks a direct ligand-binding domain but acts as a co-receptor to enhance signaling when paired with other ERBB family members. Its importance in oncology has led to the development of therapies targeting HER2, such as monoclonal antibodies and tyrosine kinase inhibitors.

Protein Structure

ERBB2 has a complex and highly conserved structure comprising distinct functional domains that contribute to its unique receptor properties and interactions:

Extracellular Domain:

• The extracellular domain (ECD) of ERBB2 is composed of approximately 625 amino acids and is organized into four subdomains (I-IV). This structure is consistent with other ERBB family members but has unique structural features that differentiate it functionally.
• Subdomains I and III: These subdomains are rich in leucine and contain ligand-binding sites in other ERBB receptors, but ERBB2 has structural changes in these regions, rendering it incapable of direct ligand binding.
• Subdomains II and IV: These cysteine-rich subdomains play a role in dimerization, a process that is essential for ERBB2 activation. Subdomain II, in particular, forms a dimerization arm that stabilizes receptor dimerization with other ERBB family members.

Transmembrane Domain:

• The transmembrane domain (TMD) consists of a single α-helix spanning the lipid bilayer. This region facilitates the stable anchoring of ERBB2 within the cell membrane and also plays a role in receptor dimerization. Mutations or alterations in this domain can affect receptor stability and signaling potential.

Juxtamembrane Domain:

• Situated between the transmembrane domain and the kinase domain, the juxtamembrane domain functions in receptor stabilization and acts as a regulatory region. Phosphorylation of this domain can influence the activation state of ERBB2.

Intracellular Kinase Domain:

• ERBB2 contains a highly conserved tyrosine kinase domain, which catalyzes the transfer of phosphate groups to specific tyrosine residues in the receptor and associated proteins. This domain is key to ERBB2’s ability to propagate intracellular signaling cascades.
• Unlike other receptors in the ERBB family, ERBB2 exists predominantly in an active conformation due to its kinase domain’s structure, even in the absence of ligand binding, which is one reason for its potency as a signaling partner.

C-terminal Tail:

• The C-terminal tail contains multiple tyrosine residues that, upon phosphorylation, serve as docking sites for downstream signaling molecules. These residues are crucial for ERBB2's role in activating signaling cascades such as the MAPK, PI3K/AKT, and STAT pathways.

Classification and Subtypes

ERBB2 is a member of the ERBB family of receptor tyrosine kinases, which share similar domain structures and signaling roles but differ in ligand binding and activation mechanisms. ERBB2 itself has no known natural ligands and instead functions as a co-receptor, enhancing the signal transduction when it forms heterodimers, particularly with EGFR (ERBB1) and ERBB3. Unlike other family members, ERBB2 is constitutively active and does not require ligand-induced dimerization, classifying it as a unique subtype in the family.

Alternative splicing events in the ERBB2 gene can generate various isoforms, although they are less well characterized than the full-length protein. The full-length ERBB2 is the primary form associated with oncogenic signaling and is the focus of most clinical research and therapeutic targeting.

Function and Biological Significance

Signal Transduction:

ERBB2 is integral to cellular signaling pathways that govern cell proliferation, survival, and differentiation. Upon heterodimerization with other ERBB receptors, ERBB2 activates several key signaling pathways:

• PI3K/AKT Pathway: Promotes cell survival and resistance to apoptosis by phosphorylating and activating proteins involved in cell cycle progression and metabolic regulation.
• MAPK Pathway: Supports cell proliferation by activating proteins in the Ras/Raf/MEK/ERK cascade, leading to transcriptional changes in genes associated with growth.
• JAK/STAT Pathway: Contributes to immune modulation and inflammatory responses, with implications in both normal and cancerous cell proliferation.

Role in Development and Homeostasis:

• ERBB2 expression is crucial during embryonic development, particularly in cardiac, neural, and mammary gland tissues. In adults, ERBB2 plays a role in maintaining cellular homeostasis and tissue repair, especially in the heart and nervous system. For example, ERBB2 signaling in cardiomyocytes is essential for maintaining cardiac function, as shown in knockout models where cardiac stress responses are impaired without ERBB2.

Oncogenic Potential:

• ERBB2 is overexpressed or amplified in many cancers, particularly breast and gastric cancers, leading to aggressive tumor growth and poor prognosis. Its role as an oncogene stems from its potent signaling capabilities, which drive uncontrolled cell proliferation and survival. Elevated levels of ERBB2 increase its likelihood of dimerizing with other ERBB receptors, amplifying signaling activity even without ligand stimulation. ERBB2’s amplification also promotes epithelial-mesenchymal transition (EMT) and metastasis.

Clinical Issues

HER2-Positive Breast Cancer:

• Amplification and overexpression of ERBB2 (HER2) occur in approximately 20-25% of breast cancers and are associated with an aggressive disease course and reduced survival rates. HER2-positive breast cancers are more likely to spread and resist standard therapies, highlighting the need for targeted treatments.
• Targeted therapies such as trastuzumab (a monoclonal antibody) and lapatinib (a tyrosine kinase inhibitor) have transformed the treatment landscape for HER2-positive breast cancer by specifically inhibiting ERBB2 signaling. Trastuzumab binds to the extracellular domain of ERBB2, blocking dimerization and promoting immune-mediated destruction of cancer cells. Newer therapies such as pertuzumab and T-DM1 (an antibody-drug conjugate) have further improved outcomes for patients with HER2-positive cancers.

Other Cancers:

• ERBB2 is also implicated in gastric, ovarian, lung, and bladder cancers, where its overexpression or gene amplification contributes to disease progression. HER2-targeted therapies have been expanded to other cancers with HER2 amplification, though effectiveness can vary depending on the tissue type and mutation context.

Cardiotoxicity:

• Anti-HER2 therapies, particularly trastuzumab, can cause cardiotoxicity, as ERBB2 signaling is important for cardiac muscle function. Cardiac side effects, such as decreased ejection fraction and heart failure, are a significant concern in HER2-targeted therapies, especially when used in combination with anthracyclines. Regular cardiac monitoring is recommended for patients receiving anti-HER2 treatments.

Resistance to HER2-Targeted Therapies:

• Resistance to therapies like trastuzumab and lapatinib can develop, often through upregulation of alternative pathways (e.g., MET or IGF-1R) or mutations in the PI3K/AKT pathway. Newer agents, such as neratinib (a pan-ERBB tyrosine kinase inhibitor) and combination therapies targeting multiple signaling pathways, are being investigated to overcome resistance.

Summary

ERBB2 (HER2) is a receptor tyrosine kinase with a crucial role in cellular growth, differentiation, and survival. Structurally, ERBB2 has an extracellular domain for dimerization with other ERBB receptors, a transmembrane domain for membrane anchoring, a juxtamembrane region for stability, a potent tyrosine kinase domain for signaling, and a C-terminal tail with phosphorylation sites essential for downstream signaling. Unique among the ERBB family, ERBB2 lacks a direct ligand but enhances signaling through heterodimerization, making it a potent activator of growth and survival pathways.

Clinically, ERBB2 is most notable for its role in HER2-positive breast cancer, where gene amplification or overexpression leads to aggressive tumor growth. Therapeutics targeting ERBB2, including trastuzumab, pertuzumab, and tyrosine kinase inhibitors, have significantly improved outcomes in HER2-positive cancers but are associated with resistance and cardiotoxicity in some patients. In addition to breast cancer, ERBB2 is implicated in other cancers, and efforts to improve HER2-targeted therapy effectiveness continue to evolve, emphasizing its importance in oncology and as a therapeutic target.