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Human epidermal growth factor receptors (HER) are potent activators of signal transduction pathways involved in cellular growth and proliferation. The HER family (also referred to as Erbb family) consists of four closely related type 1 transmembrane tyrosine kinase receptors: epidermal growth factor receptor (EGFR also known as HER1), HER2, HER3, and HER4 [1]. Each receptor consists of an extracellular domain with ligand binding property, a transmembrane lipophilic α-helical segment, and an intracellular domain with tyrosine kinase activity.

In the inactive state, HER exist as monomers with the extracellular domain in a tethered conformational state that prevents dimerization and subsequent receptor activation [2]. Binding of a ligand to the extracellular domain results in a conformational change exposing the β-hairpin arm of each domain to form pairs with other receptors [3, 4]. HER can form homo dimers (two molecules of the same receptor) or heterodimers (two molecules of different receptors from the HER family) allowing for multiple receptor combinations [5]. The formation of the HER dimer then leads to activation of the tyrosine kinase domain and cross-phosphorylation of the tyrosine residues in the C-terminal tail segment [6]. The phosphorylation provides for docking sites for recruitment for a variety of signaling molecules that contain SH2 or PTB domains and results in the activation of intracellular signaling cascades, particularly the PI3K/AKT/mTOR and the RAS/RAF/ERK pathways, as depicted in Figure 4.1(a).

Figure 4.1(a)

Schema outlining the HER2 signaling pathway and postulated site of action of major anti-HER2 therapies.

The formation of a HER dimer leads to activation of the tyrosine kinase domain and cross-phosphorylation of the tyrosine residues providing docking sites for recruitment for a variety of signaling molecules. The two principal intracellular signaling pathways of the HER family include the PI3K/AKT/mTOR pathway and the RAS/RAF/ERK pathway.

PI3K signaling is initiated when the p85 regulatory subunit of the PI3K alpha domain binds directly to the phosphotyrosine residues of the HER moiety. This leads to the phosphorylation of phosphatidylinositol 4,5-diphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 then sequentially activates phosphoinositide-dependent kinase 1 (PDK1) and AKT, which leads to phosphorylation of many other proteins, including mTOR (mammalian target of rapamycin), involved in cell survival.

ERK pathway signaling is initiated upon phosphorylation of RAS, a small GTPase, via tyrosine kinase activity. RAS in turns activates Raf which then activates mitogen-activated extracellular-signal regulated kinase (MEK1/2), and subsequently the downstream extracellular signal regulated kinase (ERK1/2). Once active, ERK1/2 phosphorylates a variety of proteins involved in cellular proliferation, differentiation and migration.

While structurally similar, each member of the HER family has unique properties. For example, in contrast with other HER family members, HER2 is a ligandless receptor and is constitutively in the conformation ready for dimerization. HER3 lacks innate kinase function, but is a potent inducer of heterodimer formation with other ...

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