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.
Highlights
Receptor tyrosine kinases (RTKs) are transmembrane proteins with an extracellular ligand binding region and an intracellular tyrosine kinase domain that play important roles both in regulation of normal cells and in the development and progression of various diseases, especially cancer
While epidermal growth factor receptor (EGFR) is endocytosed and can be degraded upon ligand-induced homodimerization, heterodimerization with ErbB2 inhibits down-regulation of EGFR [45,46], supporting the notion that ErbB2 is resistant to down-regulation
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
Summary
Receptor tyrosine kinases (RTKs) are transmembrane proteins with an extracellular ligand binding region and an intracellular tyrosine kinase domain that play important roles both in regulation of normal cells and in the development and progression of various diseases, especially cancer. Ligand binding, followed by activation of the kinase domains and initiation of signaling pathways, occur at the plasma membrane. In addition to ErbB2, the ErbB-family consists of EGFR/ErbB1, ErbB3/HER3, and ErbB4/HER4 Ligand binding induces both receptor homo- and heterodimerization, but each receptor has its specialties. ErbB2 is resistant to down-regulation, and upon ligand-induced heterodimerization it inhibits down-regulation of the dimerization partner (reviewed in [4,5]). ErbB2 plays an important role in regulation of activity and signal transduction mediated by members of the ErbB-family. Down-regulation of ErbB2 can be induced upon incubation with antibodies recognizing its extracellular domain. How such down-regulations occur is, widely debated. ErbB2 can be translocated to the nucleus and possible membrane transport pathways will be discussed
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