This EGFR-HER3 interdependency is seen in tumor cell types harboring mutationally activated EGFR as well as wild-type EGFR, revealing a central role for EGFR-HER3 signaling in this disease

This EGFR-HER3 interdependency is seen in tumor cell types harboring mutationally activated EGFR as well as wild-type EGFR, revealing a central role for EGFR-HER3 signaling in this disease. 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 depend entirely Rabbit Polyclonal to RNF149 on the development and power of predictive tools. == Background == The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) are the most extensively studied family of RTKs and strongly implicated in the pathogenesis of many types of human cancer. The family includes the four highly homologous members EGFR (HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4), sharing a structure that consists of a ligand-binding extracellular domain (ECD), an intracellular kinase domain (KD), and a c-terminal signaling tail. Signaling is mediated through ligand-induced TRC051384 receptor dimerization and transphosphorylation, leading to activation of cytoplasmic signaling pathways. The individual HER proteins have nonredundant functions and unique attributes and heterodimerization constitutes the predominant mode of signaling in this family. The functions of the third member HER3 have been least understood, and mounting evidence implicating it in human cancer TRC051384 pathogenesis have deepened interest in resolving the mysteries surrounding it. The unique attribute that separates HER3 from the other HER proteins is its evolutionary divergence at critical residues within the KD, locking it in the inactive conformation, thus devoid of catalytic kinase activity (1-3). Our traditional models of RTK function have not been able to deal with this finding, and by default, HER3 has been considered to function merely as a signaling substrate for other HER proteins, analogous to the functions of IRS1 and IRS2 with the insulin receptor. This model would appear to dismiss functionality within the HER3 KD, a concept that is difficult to reconcile in evolutionary terms. The recent landmark study revealing a highly unique mechanism underlying KD activation in the HER family now finally identifies the potential functions of a catalytically inactive KD such TRC051384 as that of HER3. In the HER family, dimerization of the KDs occurs in an asymmetric configuration leading to the allosteric activation of one KD by the other (4). In this interaction the activator KD has no catalytic role, immediately suggesting that the HER3 KD may be a highly specialized allosteric activator of its HER family partners (figure 1a). The functions of the HER3 KD as a specialized allosteric activator have been confirmed in biochemical assays (3). == Figure 1a. == TRC051384 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. In contrast to the other HER proteins, HER3 is not transforming when overexpressed or constitutively activated by continuous ligand stimulation (5) and there are currently no mutational alterations known to confer oncogenic activities to HER3. This may be due to a number of mechanisms in place that appear to function to restrain the signaling functions of HER3 (figure 1b). The absence of catalytic activity is only one such mechanism. In the absence of ligand activation, the HER3 c-terminal tail binds and covers its activation surfacein trans, restraining its.