The role of the ubiquitination-proteasome pathway in breast cancer: ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer

Abstract

Aberrant activity of growth factor receptors has been implicated in the pathogenesis of a wide variety of malignancies. The negative regulation of signaling by growth factor receptors is mediated in large part by the ubiquitination, internalization, and degradation of the activated receptor. Over the past few years, considerable insight into the mechanisms that control receptor downregulation has been gained. There are also data suggesting that mutations that lead to inhibition of downregulation of growth factor receptors could play a role in the pathogenesis of cancer. Therapies directed at enhancing the degradation of growth factor receptors offer a promising approach to the treatment of malignancies.

Figure 1

Ubiquitin (Ub)-mediated pathways of growth factor receptor (GFR) downregulation. There are two ubiquitin-mediated pathways of GFR degradation: ligand-dependent degradation (shown to the right) and ligand-independent degradation (shown to the left). Ligand-dependent degradation: upon ligand-induced activation of the mature GFR, Cbl proteins are recruited to the GFR and mediate ubiquitination, internalization, and degradation of the GFR (see text for details). Cin85, endophillins (End), and Eps 15 are involved in the internalization of the GFR. Regulatory proteins include protein kinase C (PKC) and Sprouty (spty). Ligand-independent degradation: a complex of protein chaperones (the stabilizing chaperone complex), including heat shock protein (Hsp)90, associates with both the nascent GFR in the endoplasmic reticulum and the mature GFR on the cell membrane and helps stabilize the protein. Drugs such as the benzoquinone ansamycins or tyrosine kinase inhibitor (TKIs) induce a change in the chaperone complex composition to one that favors degradation of the bound proteins (the degrading chaperone complex). The altered chaperone complex recruits an E3 ligase, which ubiquitinates the bound proteins, which in turn leads to their degradation by the proteasome (see text for details). E3 proteins are shown in green. The red color indicates current or potential agents that might enhance receptor degradation and thus be of clinical utility as treatment for cancer. E2, ubiquitin conjugation enzyme.