Human epidermal growth factor receptor 2 (HER2) intracellular domain (HER2-ICD)

The Human Epidermal Growth Factor Receptor 2 (HER2) intracellular domain (ICD) is a critical cytoplasmic region of the HER2 protein, a member of the ErbB family of receptor tyrosine kinases [1]. This domain contains the catalytic kinase core and a C-terminal tail with multiple tyrosine residues that, upon phosphorylation, serve as docking sites for signaling molecules like Shc and Grb2 [1,2]. These interactions trigger major oncogenic pathways, including the PI3K/Akt and MAPK pathways, which drive cell proliferation and survival [2]. In many cancers, particularly breast and gastric, HER2 is overexpressed or mutated, leading to constitutive ICD activity and tumor growth [2,3]. The ICD is the primary target for small-molecule tyrosine kinase inhibitors (TKIs) such as lapatinib and tucatinib, which block signaling by competing with ATP [4]. Furthermore, the ICD is highly immunogenic and contains numerous epitopes that are processed and presented on the cell surface via MHC molecules [3,5]. This makes the ICD a strategic target for cancer vaccines and T-cell therapies aimed at inducing a cellular immune response against HER2-positive tumors, potentially overcoming resistance to extracellular-targeting antibodies [3,5].

Other names

ErbB2 intracellular domainp138HER2 kinase domainCD340 intracellular domainNeu intracellular domainHER2 intracellular domain epitopes

Small molecule tyrosine kinase inhibitors bind to the ATP-binding site of the intracellular domain to prevent autophosphorylation and downstream signaling. Therapeutic vaccines utilize intracellular domain epitopes to stimulate MHC-restricted cytotoxic T-lymphocyte responses against HER2-expressing tumor cells.