Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP

Rouleau, Cecile; Fernando, Arun T. Pores; Hwang, Justin; Faure, Nathalie; Jiang, Tao; White, Elizabeth; Roberts, Thomas M.; Schaffhausen, Brian

doi:10.1128/jvi.00417-16

Cited by 14 publications

(16 citation statements)

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“…In the recent proteomic work that led to the MT-YAP story, a number of novel interactors were uncovered (8). Detailed proteomics will be needed to determine whether these or other interactions could explain the E349K phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…pInducer 20 constructs for inducible expression of wild-type MT and wild-type MT that is hemagglutinin (HA) and FLAG tagged at the C terminus have been described previously (8). pInducer MT-expressing cells were isolated after lentivirus infection and G418 selection as described previously (8).…”

Section: Mt-h-mentioning

confidence: 99%

“…pInducer MT-expressing cells were isolated after lentivirus infection and G418 selection as described previously (8).…”

Section: Mt-h-mentioning

confidence: 99%

“…Tyrosine phosphorylation (6) and phosphatidylinositol 3-kinase (PI3K) (7) are just two important areas of investigation opened by analysis of MT. Recent work showing the importance of the Hippo effector YAP (8) and protein phosphatase 2A (PP2A) A␤ isoforms (9) to polyomavirus phenotypes demonstrates the continuing value of the system. Studies of the PI3K isoform dependence in a genetically engineered MT model of breast cancer aided the design of clinical trials of p110␣ isoform-specific PI3K inhibitors (10).…”

mentioning

confidence: 99%

“…Minor tyrosine phosphorylations seem also to contribute (29). YAP and TAZ, the effectors of the Hippo signaling pathway, have recently been added to the list of important associations (8,30,31). YAP is quite important for MT transformation, since knocking it down or preventing its binding to MT affects transformation.…”

mentioning

confidence: 99%

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A Transformation-Defective Polyomavirus Middle T Antigen with a Novel Defect in PI3 Kinase Signaling

Denis

Rouleau

Schaffhausen

2017

J Virol

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Middle T antigen (MT), the principal oncoprotein of murine polyomavirus, transforms by association with cellular proteins. Protein phosphatase 2A (PP2A), YAP, Src family tyrosine kinases, Shc, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-␥1 (PLC␥1) have all been implicated in MT transformation. Mutant dl1015, with deletion of residues 338 to 347 in the C-terminal region, has been an enigma, because the basis for its transformation defect has not been apparent. This work probes the dl1015 region of MT. Because the region is proline rich, the hypothesis that it targets Src homology domain 3 (SH3) domains was tested, but mutation of the putative SH3 binding motif did not affect transformation. During this work, two point mutants, W348R and E349K, were identified as transformation defective. Extensive analysis of the E349K mutant is described here. Similar to wildtype MT, the E349K mutant associates with PP2A, YAP, tyrosine kinases, Shc, PI3 kinase, and PLC␥1. The E349K mutant was examined to determine the mechanism for its transformation defect. Assays of cell localization and membrane targeting showed no obvious difference in localization. Src association was normal as assayed by in vitro kinase and MT phosphopeptide mapping. Shc activation was confirmed by its tyrosine phosphorylation. Association of type 1 PI3K with MT was demonstrated by coimmunoprecipitation, showing both PI3K subunits and in vitro activity. Nonetheless, expression of the mutants failed to lead to the activation of two known downstream targets of PI3K, Akt and Rac-1. Strikingly, despite normal association of the E349K mutant with PI3K, cells expressing the mutant failed to elevate phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in mutant-expressing cells. These results indicate a novel unsuspected aspect to PI3K control. IMPORTANCEThe gene coding for middle T antigen (MT) is the murine polyomavirus oncogene most responsible for tumor formation. Its study has a history of uncovering novel aspects of mammalian cell regulation. The importance of PI3K activity and tyrosine phosphorylation are two examples of insights coming from MT. This study describes new mutants unable to transform like the wild type that point to novel regulation of PI3K signaling. Previous mutants were defective in PI3K because they failed to bind the enzyme and bring the activity to the membrane. These mutants recruit PI3K activity like the wild type, but fail to elevate the cellular level of PIP3, the product used to signal downstream of PI3K. As a result, they fail to activate either Akt or Rac1, explaining the transformation defect.

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Section: Discussionmentioning

confidence: 99%

Section: Mt-h-mentioning

confidence: 99%

“…pInducer MT-expressing cells were isolated after lentivirus infection and G418 selection as described previously (8).…”

Section: Mt-h-mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Transformation-Defective Polyomavirus Middle T Antigen with a Novel Defect in PI3 Kinase Signaling

Denis

Rouleau

Schaffhausen

2017

J Virol

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Wound healing and regeneration in spiny mice (Acomys cahirinus)

Okamura

Nguyen

Beier

et al. 2022

Current Topics in Developmental Biology

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The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance

2016

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Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both “On” and “Off” switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the “On” position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective “Off” switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.

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Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP

Cited by 14 publications

References 100 publications

A Transformation-Defective Polyomavirus Middle T Antigen with a Novel Defect in PI3 Kinase Signaling

A Transformation-Defective Polyomavirus Middle T Antigen with a Novel Defect in PI3 Kinase Signaling

Wound healing and regeneration in spiny mice (Acomys cahirinus)

The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance

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