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Gasser, Jessica

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Gasser

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Jessica

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Gasser, Jessica
Author's Publications: search.filters.isAuthorOfPublication.8a589811-d65c-439f-83b3-e184ed832758

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    Serum and Glucocorticoid-Regulated Kinase Signaling in Breast Cancer
    (2014-02-25) Gasser, Jessica; Toker, Alex; Cantley, Lewis; Harper, Wade; Blenis, John; Schaffhausen, Brian; Zhao, Jean; Hahn, William
    Oncogenic activating mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI 3-K), are highly prevalent in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, though the mechanisms by which PI 3-K mediates tumorigenic signals in an Akt-independent manner remain obscure. My studies show that the serum and glucocorticoid-regulated kinases (SGKs) can function as effectors of PI 3-kinase and transduce signals to phenotypes associated with malignancy. We show that SGK3 is amplified in breast cancer and identify the mechanism by which SGK3 is activated downstream of PIK3CA, specifically through the catalytic activity of the phosphoinositide phosphatase INPP4B. Expression of INPP4B promotes SGK3 activation and in turn inhibits Akt phosphorylation. In breast cancer cell lines with elevated levels of INPP4B, SGK3 is required for proliferation in 3D and also for invasive migration. SGK3 phenotypes are in part mediated by phosphorylation of the substrate protein N-myc downstream regulated 1 (NDRG1), an established metastasis suppressor. The phosphorylation of NDRG1 leads to recruitment by F-box and WD repeat domain-containing 7 (FBW7), the substrate recognition domain of the Skp, Cullin, F-box containing (SCF) complex. Binding of Fbw7 to NDRG1 promotes its polyubiquitination and subsequent degradation by the 26S proteasome. By contrast, our studies also show that the related SGK1 isoform is polyubiquitinated by the functional E3 ubiquitin ligase Rictor-Cullin-1 complex, leading to SGK1 degradation. Proteasomal degradation of SGK1 by Rictor-Cullin-1is the first identified mTORC2-independent function of the Rictor protein. Moreover, the deregulation of SGK1 ubiquitination highlights a mechanism of SGK1 overexpression in breast cancers.
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    The CDK Inhibitor CR8 Acts as a Molecular Glue Degrader That Depletes Cyclin K
    (Springer Science and Business Media LLC, 2020-06-03) Słabicki, Mikołaj; Kozicka, Zuzanna; Petzold, Georg; Li, Yen-Der; Manojkumar, Manisha; Bunker, Richard D.; Donovan, Katherine A.; Sievers, Quinlan; Koeppel, Jonas; Suchyta, Dakota; Sperling, Adam S.; Fink, Emma C.; Gasser, Jessica; Wang, Li R.; Corsello, Steven M.; Sellar, Rob S.; Jan, Max; Gillingham, Dennis; Scholl, Claudia; Fröhling, Stefan; Golub, Todd; Fischer, Eric S.; Thomä, Nicolas H.; Ebert, Benjamin
    Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation. Unlike traditional enzyme inhibitors, such molecular glue degraders act sub-stoichiometrically to catalyse rapid depletion of previously inaccessible targets. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Through systematic mining of databases for correlations between the cytotoxicity of 4,518 compounds and E3 ligase expression levels across hundreds of human cancer cell lines, we identified CR8, a cyclin-dependent kinase (CDK) inhibitor, as a compound that acts as a molecular glue degrader. A solvent-exposed pyridyl moiety of CR8, in its CDK-bound form, induces CDK12-cyclin K complex formation with DDB1, the CUL4 adaptor protein, bypassing the requirement for a substrate receptor and presenting cyclin K (cycK) for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy to turn target binders into molecular glues.