HER3 comes of age: new insights into its functions and role in signaling, tumor biology, and cancer therapy

Abstract

The human epidermal growth family (HER) of tyrosine kinase receptors underlies the pathogenesis of many types of human cancer. The oncogenic functions of three of the HER proteins can be unleashed through amplification, overexpression, or mutational activation. This has formed the basis for the development of clinically active targeted therapies. However, the third member HER3 is catalytically inactive, not found to be mutated or amplified in cancers, and its role and functions have remained shrouded in mystery. Recent evidence derived primarily from experimental models now seems to implicate HER3 in the pathogenesis of several types of cancer. Furthermore, the failure to recognize the central role of HER3 seems to underlie resistance to epidermal growth factor receptor (EGFR)- or HER2-targeted therapies in some cancers. Structural and biochemical studies have now greatly enhanced our understanding of signaling in the HER family and revealed the previously unrecognized activating functions embodied in the catalytically impaired kinase domain of HER3. This renewed interest and mechanistic basis has fueled the development of new classes of HER3-targeting agents for cancer therapy. However, identifying HER3-dependent tumors presents a formidable challenge and the success of HER3-targeting approaches depends entirely on the development and power of predictive tools.

Figure 1a

Schematic representation of HER3 engaged in dimerization and actively signaling. The dimer is reinforced by interaction of the juxta-membrane segments, forming a stabilizing latch. Through its activating interface, HER3 engages and allosterically activates its kinase partners, in this case HER2. Phosphorylation of its c-terminal tail leads to recruitment of adapter proteins leading to activation of Ras and PI3K. Recruitment and activation of PI3K leads to phosphorylation of membrane phosphoinositides producing PIP3, which in turn docks the PH domain-containing proteins PDK1 and Akt. Membrane-bound Akt is phosphorylated and activated by PDK1 and Tor-complex 2 (TORC2). Activated Akt proceeds to phosphorylate a plethora of cellular substrates involved in diverse biological processes.

Figure 1b

Schematic representation of mechanisms in place that restrain HER3 from signaling. If not transcriptionally, post-transcriptionally, or post-translationally repressed, much of HER3 is sequestered into clusters mediated through N-lobe head-to-head interactions and reciprocal c-tail interactions (3). The proximal c-terminal tails bind and cover the activating interface of the KD, obstructing its allosteric activating function. Even when not sequestered, HER3 is incapable of self-activation as it lacks the receiving interface for allosteric activation and its active site is permanently locked in the inactive state. It can only engage as the activating partner with the other HER family members, as shown in 1a.

Figure 1c

Schematic depiction of the 14 tyrosines on the c-terminal signaling tail of HER3. Whether or not all of these tyrosines undergo phosphorylation in cells has not been confirmed. But phospho-peptide binding studies have identified many SH2 and PTB domains that are capable of high affinity binding to these phosphotyrosine sites as indicated. Only binding activities with nanomolar range Kd are shown here. The detailed binding data are available from the data sources (48, 49). The six PI3K binding sites are confirmed to undergo phosphorylation and can mediate the interaction with each of the three regulatory subunits of PI3K. Additional tyrosines within the kinase domain show binding activity in phosphopeptide assays, but are not shown here.