Melanoma antigen-A11 regulates substrate-specificity of Skp2-mediated protein degradation

Abstract

Melanoma antigen-A11 (MAGE-A11) is a proto-oncogene involved in androgen receptor signaling and androgen-dependent cell growth. In this report we provide evidence that MAGE-A11 interacts with Skp2 (S phase kinase-associated protein), the substrate recognition protein of the Skp1-Cullin1-F-box E3 ubiquitin ligase, and with Skp2 binding protein, cyclin A. A similar cyclin A binding motif in MAGE-A11 and Skp2 was consistent with a competitive relationship between MAGE-A11 and Skp2 in binding cyclin A. Skp2 inhibited MAGE-A11 interaction with cyclin A. Differential effects of MAGE-A11 on Skp2-mediated protein degradation were also revealed. MAGE-A11 increased Skp2-mediated degradation of cyclin A and retinoblastoma-related protein p130. In contrast, MAGE-A11 decreased Skp2-mediated degradation of E2F1 and Skp2 self-ubiquitination. Stabilization of E2F1 by MAGE-A11 was associated with sequestration and inactivation of Skp2 through the formation of an E2F1-MAGE-A11-Skp2 complex. We conclude that direct interactions of MAGE-A11 with Skp2 and cyclin A regulate the substrate-specificity of Skp2-mediated protein degradation.

Epigenetic regulation of MAGE family in human cancer progression-DNA methylation, histone modification, and non-coding RNAs

“…However, it does not affect p53 turnover mediated by MDM2 [ 36 ]. MAGE-A11 interacts with Skp2, the substrate recognition protein of the Skp1-Cullin1-F-box E3 ubiquitin ligase, and increases Skp2-mediated degradation of cyclin A and p130, but decreases Skp2-mediated degradation of E2F1 and Skp2 self-ubiquitination by sequestering and inactivating Skp2 via forming an E2F1-MAGE-A11-Skp2 complex [ 37 ].…”

Cellular and disease functions of the Prader–Willi Syndrome geneMAGEL2

“…In addition, MAGEs have been reported to alter substrate specificity of ligases, such that MRL complexes have a different spectrum of targets than the E3 RING alone. Mechanistically MAGE proteins can directly bind substrates and recruit them to the E3 ligase for ubiquitination, such as MAGE-A3/6 binding AMPK and mediating its ubiquitination by TRIM28 (25) or change substrate preference in the case of MAGE-A11 and Skp2 (35). Also, MAGEs can alter the subcellular localization of the ligase allowing it to find novel substrates, such as MAGEL2 directing TRIM27 to endosomes for ubiquitination WASH (26).…”

A Comprehensive Guide to the MAGE Family of Ubiquitin Ligases

“…A subsequent study found that MAGE-A11 interacts with Skp2, an F-box domain substrate recognition protein of the SCF CRL [53]. In this case, MAGE-A11 regulates substrate specificity of Skp2, such that MAGE-A11 enhances Skp2-mediated degradation of cyclin A and the retinoblastoma-related protein p130, but inhibits Skp2-mediated degradation of the E2F1 transcription factor [53].…”

“…In this case, MAGE-A11 regulates substrate specificity of Skp2, such that MAGE-A11 enhances Skp2-mediated degradation of cyclin A and the retinoblastoma-related protein p130, but inhibits Skp2-mediated degradation of the E2F1 transcription factor [53]. The authors account the differential effects of MAGE-A11 on Skp2 by proposing a competitive relationship between MAGE-A11 and Skp2 in binding cyclin A [53]. Collectively these data suggest that MAGEs may regulate cell cycle progression by modulating SCF ubiquitin ligase activity and substrate recognition.…”