The ubiquitin-proteasome system (UPS) is a complex cellular machine that is responsible for maintaining normal homeostasis by targeting misfolded and damaged proteins for degradation. It is characterized by a multienzyme cascade that catalyzes the addition of ubiquitin molecules onto the target proteins. A ubiquitin-activating enzyme E1, a conjugation enzyme E2, and a multi-domain ligase E3 form the complex triad that controls the ubiquitylation of substrate proteins. The substrates for the UPS play important roles in cell signaling pathways, and, in several diseases, linked to neurodegeneration and cancer also, E3 ligases that are part of the UPS enzyme cascade can be dysregulated and function as oncogenes. E3 ligases promote ubiquitination of tumor suppressor proteins leading to their degradation by the 26S proteasome. The RING E3 ligase subfamily contains evolutionarily conserved F-box and SOCS-box proteins that recognize and bind substrates through a characteristic SPRY domain. The RING E3 ligases like Fbxo45 specifically recognize the tumor suppressor protein Par-4 via a consensus VASA-like ELNNNL binding motif, which is located within the pro-apoptotic PAF domain of Par-4. In therapy-sensitive tumors, the PAF domain undergoes caspase-induced cleavage and acts as a decoy substrate for Fbxo45, thereby rescuing Par-4 from ubiquitination. The degradation of Par-4 leads to tumorigenesis, drug resistance, and poor overall survival in several cancers. Greater understanding of E3 ligase interactions with tumor suppressor proteins like Par-4 can drive the development of novel therapeutic approaches to better regulate the UPS in cancer and improve survival outcomes in patients.

Original languageEnglish
Title of host publicationTumor Suppressor Par-4
Subtitle of host publicationStructural Features, Molecular Mechanisms and Function
Number of pages33
ISBN (Electronic)9783030735722
StatePublished - Jan 1 2022

Bibliographical note

Publisher Copyright:
© Springer Nature Switzerland AG 2022.


  • COP1 degron
  • E3 ligases
  • F-box
  • Fbxo45
  • PAF
  • Par-4
  • RING
  • Skp1-Cullin-F-box subfamily
  • TRIM-21
  • Ubiquitinases

ASJC Scopus subject areas

  • General Medicine


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