The ubiquitin-proteasome system meets angiogenesis

Abstract

A strict physiological balance between endogenous proangiogenic and antiangiogenic factors controls endothelial cell functions, such that endothelial cell growth is normally restrained. However, in pathologic angiogenesis, a shift occurs in the balance of regulators, favoring endothelial growth. Much of the control of angiogenic events is instigated through hypoxia-induced VEGF expression. The ubiquitin-proteasome system (UPS) plays a central role in fine-tuning the functions of core proangiogenic proteins, including VEGF, VEGFR-2, angiogenic signaling proteins (e.g., the PLCγ1 and PI3 kinase/AKT pathways), and other non-VEGF angiogenic pathways. The emerging mechanisms by which ubiquitin modification of angiogenic proteins control angiogenesis involve both proteolytic and nonproteolytic functions. Here, I review recent advances that link the UPS to regulation of angiogenesis and highlight the potential therapeutic value of the UPS in angiogenesis-associated diseases.

Figure 1

Schematic presentation of tumor-induced angiogenesis and choroidal neovascularization as manifested in wet AMD. Expression of VEGF is responsible for induction of angiogenesis which is associated with tumor progression and worsening of wet AMD.

Figure 2

VEGF superfamily ligands and receptors: The schematic of VEGF ligands, their interaction with VEGF receptors are shown.

Figure 3

The schematic of ubiquitin-proteasome system is shown. Ubiquitin (Ub) is activated by the ubiquitin-activating enzyme (E1) followed by its transfer to a ubiquitin-conjugating enzyme (E2). E2 transfers the activated ubiquitin moieties to the protein substrate that is bound specifically to a particular ubiquitin ligase (E3). The transfer of ubiquitin takes place either directly in the case of RING finger ligases or via an additional thiol-ester intermediate on the ligase in case of HECT domain ligases. Repeated conjugation of ubiquitin moieties to one another generates a polyubiquitin chain that serves as the binding and degradation signal for the 26S proteasome. The protein substrate is degraded generating short peptides, and free ubiquitin which could be further re-used.

Figure 4

Role of pVHL in expression of VEGF and angiogenesis: In the presence of oxygen proline residues in the oxygen-dependent degradation (ODD) domain of HIF are hydroxylated. This allows HIF-α to interact with pVHL. The interaction between HIF and pVHL causes degradation of HIF through ubiquitination. In response to low oxygen (i.e., hypoxia), pVHL is S- nitrosylated, preventing HIF-α to interact with and pVHL and the degradation of HIF-α is disallowed. HIF-α stimulates gene expression such as VEGF which stimulates angiogenesis as manifested in cancer progression. S-nitrosylation is the covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine.

Figure 5

Regulation of core angiogenic proteins by ubiquitin E3 ligases. Expression of VEGF is regulated by activity of pVHL. βTrcp1 ubiquinates VEGFR-2 and subjects it for proteasomal degradation. c-Cbl catalyzes ubiquitination of numerous angiogenic signaling proteins including VEGFR-1, Eph, Tie2 and PLCγ1. AKT abundance and activity is regulated TRAF6, CHIP and TTC3. Itch regulates degradation of Notch1 receptor.