Receptor tyrosine-protein kinase erbB-2 (HER2) intracellular kinase domain (HER2)

The HER2 (Human Epidermal Growth Factor Receptor 2) intracellular kinase domain is the catalytic region of the Receptor tyrosine-protein kinase erbB-2, a member of the epidermal growth factor receptor (EGFR) family [Wikipedia, PMC]. Unlike other family members, HER2 lacks a known ligand-binding site and functions as a constitutive signaling partner that heterodimerizes with other ligand-bound HER receptors to activate downstream pathways, including PI3K/Akt and MAPK/ERK [NIH, PMC]. Overexpression or gene amplification of HER2 is a well-characterized driver in approximately 20-30% of breast cancers and a significant portion of gastric and esophageal adenocarcinomas, leading to aggressive tumor growth and poor prognosis [NIH, IntechOpen]. Additionally, somatic mutations within the kinase domain, such as exon 20 insertions, have emerged as critical oncogenic drivers in non-small cell lung cancer [PubMed, PMC]. Small molecule tyrosine kinase inhibitors (TKIs), such as lapatinib, neratinib, and tucatinib, target this domain by competitively inhibiting ATP binding, thereby preventing receptor autophosphorylation and halting oncogenic signaling [Drugs.com, PMC]. Despite the success of these targeted therapies, clinical challenges include the development of resistance through secondary mutations and safety concerns such as cardiotoxicity and gastrointestinal toxicity [NIH, StatPearls].

Other names

ERBB2 [Wikipedia]CD340 [Wikipedia]HER-2 [NIH]HER-2/neu [NIH]NEU [Wikipedia]NGL [Wikipedia]TKR1 [Wikipedia]erb-b2 receptor tyrosine kinase 2 [Wikipedia]

Small molecule tyrosine kinase inhibitors (TKIs) competitively bind to the ATP-binding site within the intracellular kinase domain of the HER2 receptor, preventing autophosphorylation and inhibiting downstream signaling pathways like PI3K/Akt and MAPK/ERK [PMC, Drugs.com].