title: The role of Cullin3-mediated ubiquitination of the catalytic subunit of PP2A in TRAIL signaling.
abstract: Protein phosphatase 2A (PP2A) is the major serine-threonine phosphatase that regulates a number of cell signaling pathways. PP2A activity is controlled partially through protein degradation; however, the underlying mechanism is not fully understood. Here we show that PP2A/C, a catalytic subunit of PP2A, is degraded by the Cullin3 (Cul3) ligase-mediated ubiquitin-proteasome pathway. In response to death receptor signaling by tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL), PP2A/C, caspase-8 and Cul3, a subunit of the cullin family of E3 ligases, are recruited into the death-inducing signaling complex (DISC) where the Cul3 ligase targets PP2A/C for ubiquitination and subsequent degradation. Functionally, knockdown of PP2A/C expression by siRNA or pharmacological inhibition of PP2A activity increases TRAIL-induced apoptosis. In cancer cells that have developed acquired TRAIL resistance, PP2A phosphatase activity is increased, and PP2A/C protein is resistant to TRAIL-induced degradation. Thus, this work identifies a new mechanism by which PP2A/C is regulated by Cul3 ligase-mediated degradation in response to death receptor signaling and suggests that inhibition of PP2A/C degradation may contribute to resistance of cancer cells to death receptor-induced apoptosis.
authors.affiliation: a Departments of Oncology and Pathology; Karmanos Cancer Institute ; Wayne State University School of Medicine ; Detroit , MI USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Jun-Ying
authors.initials: JY
authors.lastname: Zhou
authors.forename: Zhengfan
authors.initials: Z
authors.lastname: Xu
authors.forename: Dhong-Hyo
authors.initials: DH
authors.lastname: Kho
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
authors.forename: Gen Sheng
authors.initials: GS
authors.lastname: Wu
mesh_terms: D020134:Catalytic Domain / Q000502:physiology*; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D054648:Protein Phosphatase 2
keywords: Cullin3; PP2A; TRAIL; apoptosis resistance; ubiquitination