Protein Phosphatase 2A Isoforms Utilizing Aβ Scaffolds Regulate Differentiation through Control of Akt Protein

Hwang, Justin; Jiang, Tao; Kulkarni, Shreya; Faure, Nathalie; Schaffhausen, Brian

doi:10.1074/jbc.m113.497644

Cited by 20 publications

(23 citation statements)

References 49 publications

(74 reference statements)

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“…Figure 7B confirms this by showing that the Akt inhibitor MK2206 completely blocks differentiation. The ability of PyST to block differentiation has also been strongly connected to inhibition of Akt activity (8). Knockdown of YAP by itself (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The important question is how YAP binding contributes to PyST phenotypes. A requirement for PP2A interaction has been demonstrated for a variety of PyST functions (6,7,45), including C2C12 myoblast differentiation (7,8). To test the role of YAP binding in a PyST differentiation block, C2C12 cells expressing wild-type or mutant PySTs were prepared and allowed to differentiate for 9 days.…”

Section: Resultsmentioning

confidence: 99%

“…3T3 cells were used because they are a traditional, well-studied substrate for polyomavirus. 3T3-L1 preadipocytes and C2C12 myoblasts are well-characterized differentiation systems used previously in our PyST experiments (7,8 3 , and either 10% fetal bovine serum (FBS) (16000044; Invitrogen) or 10% calf serum (CS) (26170043; Invitrogen). Cells that were grown in 10% FBS medium include C2C12 cells, 3T3-L1 cells, 293T cells, and Phoenix Ampho cells, while NIH 3T3 cells were grown in medium with 10% CS.…”

Section: Methodsmentioning

confidence: 99%

“…It is a "professional killer," causing cell death via mitotic catastrophe even at low levels of expression. PyST blocks differentiation to adipocytes, myocytes, or osteoblasts (7,8). From a virology perspective, it is interesting that these effects are not generally observed with simian virus 40 (SV40) small t antigen (SV40ST).…”

mentioning

confidence: 99%

“…A comparison of SV40 to polyomavirus showed that only PyST strongly associated with the A␤ scaffold subunit of the PP2A family of enzymes (7). Subsequent work showed the importance of the A␤ isoform in regulation of survival and differentiation, at least in part because of its effects on Akt (8). Earlier work suggested that all three T antigens, including PyST, could bind to TAZ (9), an interaction affecting the host range of the virus.…”

mentioning

confidence: 99%

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Polyomavirus Small t Antigen Interacts with Yes-Associated Protein To Regulate Cell Survival and Differentiation

Hwang

Fernando

Faure

et al. 2014

J Virol

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Murine polyomavirus small t antigen (PyST) regulates cell cycle, cell survival, apoptosis, and differentiation and cooperates with middle T antigen (MT) to transform primary cells in vitro and in vivo. Like all polyomavirus T antigens, PyST functions largely via its interactions with host cell proteins. Here, we show that PyST binds both Yes-associated protein 1 (YAP1) and YAP2, integral parts of the Hippo signaling pathway, which is a subject of increasing interest in human cancer. The transcription factor TEAD, which is a known target of YAP, is also found in PyST complexes. PyST enhanced YAP association with protein phosphatase 2A (PP2A), leading to decreased YAP phosphorylation. PyST increased YAP levels by decreasing its degradation. This effect was mediated by a reduction in YAP association with ␤-transducin repeat protein (␤TRCP), which is known to regulate YAP turnover in a phosphorylation-dependent manner. Genetic analysis has identified PyST mutants defective in YAP binding. These mutants demonstrated that YAP binding is important for PyST to block myoblast differentiation and to synergize with the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) to promote cell death in 3T3-L1 preadipocytes placed under differentiation conditions. In addition to YAP binding, both of these phenotypes require PyST binding to PP2A. IMPORTANCEThe Hippo/YAP pathway is a highly conserved cascade important for tissue development and homeostasis. Defects in this pathway are increasingly being associated with cancer. Polyomavirus small t antigen is a viral oncogene that cooperates with middle T antigen in transformation. On its own, small t antigen controls cell survival and differentiation. By binding YAP, small t antigen brings it together with protein phosphatase 2A. This work shows how this association of small t antigen with YAP is important for its effects on cell phenotype. It also suggests that PyST can be used to characterize cellular processes that are regulated by YAP.

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Section: Resultsmentioning

confidence: 98%