The Mysterious Ways of ErbB2/HER2 Trafficking

Abstract

The EGFR- or ErbB-family of receptor tyrosine kinases consists of EGFR/ErbB1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Receptor activation and downstream signaling are generally initiated upon ligand-induced receptor homo- or heterodimerization at the plasma membrane, and endocytosis and intracellular membrane transport are crucial for regulation of the signaling outcome. Among the receptors, ErbB2 is special in several ways. Unlike the others, ErbB2 has no known ligand, but is still the favored dimerization partner. Furthermore, while the other receptors are down-regulated either constitutively or upon ligand-binding, ErbB2 is resistant to down-regulation, and also inhibits down-regulation of its partner upon heterodimerization. The reason(s) why ErbB2 is resistant to down-regulation are the subject of debate. Contrary to other ErbB-proteins, mature ErbB2 needs Hsp90 as chaperone. Several data suggest that Hsp90 is an important regulator of factors like ErbB2 stability, dimerization and/or signaling. Hsp90 inhibitors induce degradation of ErbB2, but whether Hsp90 directly makes ErbB2 endocytosis resistant is unclear. Exposure to anti-ErbB2 antibodies can also induce down-regulation of ErbB2. Down-regulation induced by Hsp90 inhibitors or antibodies does at least partly involve internalization and endosomal sorting to lysosomes for degradation, but also retrograde trafficking to the nucleus has been reported. In this review, we will discuss different molecular mechanisms suggested to be important for making ErbB2 resistant to down-regulation, and review how membrane trafficking is involved when down-regulation and/or relocalization of ErbB2 is induced.

Figure 1

Conformation of monomeric and dimeric ErbB-proteins. While the extracellular region of ErbB2 constitutively adopts an open conformation, EGFR, ErbB3, and ErbB4 depend on ligand binding to change from a closed to an open conformation and to participate in dimerization. In dimers, the kinase domains (KDs) interact in an asymmetric fashion where the C-terminal of one KD interacts with the N-terminal of the other. I-IV refer to the respective domains in the extracellular region of the receptors.

Figure 2

Four models for ErbB2 resistance to down-regulation. (A) Internalization of ErbB2 is restricted due to a lack of internalization signals, or because interaction with Cdc37-Hsp90 induces a conformation where internalization signals are hidden; (B) ErbB2 is retained at the plasma membrane due to interaction with proteins like flotillins and possibly other raft components; (C) Expression of ErbB2 inhibits the formation of clathrin-coated pits; (D) Internalization of ErbB2 is not inhibited, but ErbB2 in endosomes recycles rapidly back to the plasma membrane. Interaction with Hsp90 has been suggested to sequester ErbB2 homodimers, but for simplicity only monomeric ErbB2 is drawn in the figure. Different internalization pathways may be involved, but also for simplicity, only clathrin-dependent internalization is illustrated.

Figure 3

Roles for ubiquitination in ErbB2 down-regulation. Inhibition of Hsp90 causes recruitment of Hsp70 and CHIP and/or CUL5 which induce ubiquitination of ErbB2. Ubiquitination can itself serve as signal for internalization and endosomal sorting of ErbB2 (A), or it can induce proteasome-mediated cleavage of the intracellular domain followed by internalization and endosomal sorting of ErbB2 (B).