The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics

Abstract

Many types of human cancer are characterized by deregulation of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors. In some cancers, genomic events causing overactivity of individual HER family members are etiologically linked with the pathogenesis of these cancers, and constitute the driving signaling function underlying their tumorigenic behavior. HER3 stands out among this family as the only member lacking catalytic kinase function. Cancers with driving HER3 amplifications or mutations have not been found, and studies of its expression in tumors have been only weakly provocative. However, substantial evidence, predominantly from experimental models, now suggest that its non-catalytic functions are critically important in many cancers driven by its' HER family partners. Furthermore, new insights into the mechanism of activation in the HER family has provided clear evidence of functionality in the HER3 kinase domain. The convergence of structural, mechanistic, and experimental evidence highlighting HER3 functions that may be critical in tumorigenesis have now led to renewed efforts towards identification of cancers or subtypes of cancers wherein HER3 function may be important in tumor progression or drug resistance. It appears now that its failure to earn the traditional definition of an oncogene has allowed the tumor promoting functions of HER3 to elude the effects of cancer therapeutics. But experimental science has now unmasked the unpretentious role of HER3 in cancer biology, and the next generation of cancer therapies will undoubtedly perform much better because of it.

Figure 1

Schematic representation of the activating functions of HER3. When bound by ligand, the HER3 extracellular domain (ECD) adopts a conformation that is highly favorable for dimerization with other HER family members. Dimerization is shown here with HER2, but is similar with all other HER family members. When dimerized with HER2, the HER3 kinase domain interacts in an asymmetrical mode with the HER2 kinase domain. This allosteric interaction activates the HER2 kinase domain. The activated HER2 kinase domain phosphorylates the c-terminal tail of HER3, which leads to the generation of intracellular signaling. In the inactivate state, the HER3 kinase domain is engaged in homotypic interactions including intra-dimer N-lobe interactions and cross-dimer C-lobe-c-tail interactions that potentially create daisy chain clusters of inactive HER3 molecules. The conformation of the HER3 ECD in these clusters is not well understood and speculated in this schematic.

Figure 2

Schematic representation of the feedback regulation of HER3 by Akt. When phosphorylated, the HER3 c-terminal tail binds the PI3K heterodimer, recruiting it to the membrane and resulting in the phosphorylation of membrane phosphoinositides and ultimate generation of membrane phosphatidylinositol triphosphate (PIP3). Akt and PDK1 dock to the membrane PIP3 via their PH domains. The phosphorylation of the activation loop of Akt by PDK1, and the phosphorylation of the hydrophobic motif of Akt by mTor leads to the full activation of Akt. Akt phosphorylates numerous cytoplasmic substrates. At least in some cancers, activated Akt reciprocally regulates HER3 signaling functions, completing a negative feedback loop that functions to preserve HER3 and consequent Akt signaling, vital for tumorigenic survival.