Defective downregulation of receptor tyrosine kinases in cancer

Abstract

Most growth factors control cellular functions by activating specific receptor tyrosine kinases (RTKs). While overactivation of RTK signalling pathways is strongly associated with carcinogenesis, it is becoming increasingly clear that impaired deactivation of RTKs may also be a mechanism in cancer. A major deactivation pathway, receptor downregulation, involves ligand-induced endocytosis of the RTK and subsequent degradation in lysosomes. A complex molecular machinery that uses the small protein ubiquitin as a key regulator assures proper endocytosis and degradation of RTKs. Here we discuss evidence that implicates deregulation of this machinery in cancer.

Figure 1

Mechanism of endocytic downregulation of RTKs. The figure illustrates RTK downregulation, with EGFR as an example. Ligand binding triggers receptor autophosphorylation via receptor dimerization. c-Cbl associates with the tyrosine-phosphorylated RTK and mediates its multi-ubiquitination. This facilitates endocytosis of the receptor via clathrin-coated pits. Proteins such as Epsin, Eps15 and Hip1 may be involved in cargo recruitment into clathrin-coated pits. Clathrin polymerization is catalysed by AP-180/CALM, and vesicle formation is facilitated by Dynamin and Endophilin. The endocytic vesicle uncoats (facilitated by Synaptojanin) and fuses with an early endosome, by a mechanism catalysed by the small GTPase Rab5 and its effectors. At the early endosome, the ubiquitinated RTK is sorted into a ‘bilayered' clathrin coat, probably by associating with ubiquitin-binding proteins such as Hrs and STAM. From here, the RTK is sorted into intraluminal vesicles of the endosome, in a process mediated by ESCRT-I (whose subunit Tsg101 binds Hrs as well as ubiquitin), ESCRT-II and ESCRT-III. The RTK is probably dephosphorylated and deubiquitinated during this sorting step. From the early endosome, a multivesicular body (MVB)/endosomal carrier vesicle is formed in an Annexin-II-dependent fashion (Gruenberg and Stenmark, 2004), which ultimately fuses with a late endosome or a lysosome. Intraluminal vesicles with their content are then degraded by lysosomal hydrolases. Ubiquitin-binding/monoubiquitinated proteins are in red, proteins found as oncogenic fusion proteins (see Table I) are in italics, and proteins experimentally implicated in cancer (see Table II) are in bold. A recycling pathway from the early endosome to the plasma membrane, which is followed by non-ubiquitinated membrane proteins, is indicated by dashed arrows. For simplicity, a number of known components of the endocytosis machinery, including specific lipids (Conner and Schmid, 2003), have been omitted from the figure. Note that RTKs can also be endocytosed from other invaginations than clathrin-coated pits, but the significance of this alternative internalization in RTK downregulation is not known (Gonzalez-Gaitan and Stenmark, 2003).