Plakophilin-2 Promotes Activation of Epidermal Growth Factor Receptor

Abstract

While growth factor-driven dimerization of receptor tyrosine kinases (RTKs) is a simple and intuitive mechanism of activating RTKs, K.-I. Arimoto et al. (Mol. Cell. Biol. 34:3843–3854, 2014, doi:10.1128/MCB.00758-14) describe a novel means of promoting the activity of RTKs. Namely, plakophilin-2 (PKP2) associates with the epidermal growth factor receptor (EGFR) and enhances its ligand-dependent and ligand-independent activity. This discovery suggests that antagonizing PKP2 may be a new therapeutic opportunity to combat tumors in which activation of EGFR contributes to pathogenesis.

TEXT

While growth factor-driven dimerization of receptor tyrosine kinases (RTKs) is a simple and intuitive mechanism of activating RTKs, in this issue of Molecular and Cellular Biology, Arimoto et al. (1) describe a novel means of promoting the activity of RTKs. Namely, plakophilin-2 (PKP2) associates with the epidermal growth factor (EGF) receptor (EGFR) and enhances both ligand-dependent and ligand-independent activity of this RTK. This discovery brings to light the possibility that antagonizing PKP2 may be a new therapeutic opportunity to combat diseases such as solid tumors in which activation of EGFR contributes to pathogenesis.

PKP2 belongs to a 3-member family of proteins that can be found in multiple locations within cells, including at desmosomes, which contribute to cell-cell junctions along the basolateral face. PKP2 is the only plakophilin family member that promotes activation of EGFR, and overexpression of PKP2 is associated with several types of solid tumors in humans. Furthermore, Arimoto et al. (1) demonstrated that reducing expression of PKP2 in a human breast tumor cell line attenuated the ability of such cells to proliferate and form tumors in mice.

EGF-mediated activation of EGFR has been an area of ongoing investigation by multiple laboratories, and hence our appreciation of this mechanism continues to improve (2–5). In the absence of EGF, the kinase activity of EGFR is inhibited by its interaction with the plasma membrane. EGF activates EGFR by overcoming this inhibition. More specifically, EGF binding to the extracellular domain triggers an interaction between transmembrane helixes that facilitates an antiparallel association between the juxtamembrane domains and thereby derepresses the EGFR's kinase activity.

While Arimoto et al. (1) demonstrated that the N terminus of PKP2 associates with the cytoplasmic domain of EGFR and that this interaction is strong enough to survive immunoprecipitation, how PKP2 promotes activation of EGFR remains an open issue. Since one of the subcellular locations of PKP2 is the desmosome, it may enhance the activity of EGFR by concentrating EGFRs in a subcellular location that is more conducive to activation (Fig. 1). Similarly, it would be good to learn whether PKP2 contributes to derepressing the kinase activation of EGFR or whether it is acting by an alternative mechanism.

FIG 1.

PKP2 promotes activation of EGFR. In the center is a desmosome, which is an essential element of the basolateral junction between two cells. Plakophilin-2 (PKP2) associates with both the desmosomes and the epidermal growth factor receptor (EGFR). EGFRs that are associated with PKP2 are more active (indicated by more phosphorylation) than EGFRs that are not. While not illustrated in this diagram, PKP2 also promotes the activity of EGFRs that are engaged by EGF.

The report by Arimoto et al. (1) is yet another reminder that direct binding of traditional ligands (such as growth factors) is not the only means of activating RTKs. This concept appears particularly relevant in diseases which involve nontraditional activation of RTKs. For instance, intracellular tyrosine kinases such as Src family kinases activate RTKs, as do circulating antibodies and certain viral proteins that physically associate with RTKs (6–9). Furthermore, resistance to inhibitors of specific RTKs involves activation of alternative RTKs, which may not involve a traditional ligand (10). Taken together, these observations underscore the slowly emerging concept that there are multiple ways to engage RTKs and that a better appreciation of the spectrum of such options emerges when a cell's viability is challenged.