STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells
| Autor: | Emily Damato, Kim Stegmaier, Christian Berrios, Pablo Tamayo, Ole Gjoerup, James A. DeCaprio, Jong Wook Kim, Michael P. Washburn, Laurence Florens, Amy E. Schade, Amanda Balboni Iniguez, Huwate Yeerna, Guillaume Adelmant, Miju Kim, Nathanael S. Gray, William C. Hahn, Jarrod A. Marto |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
environment and public health STRIPAK Mice Phosphoprotein Phosphatases Biology (General) Cancer Biology chemistry.chemical_classification Kinase General Neuroscience Intracellular Signaling Peptides and Proteins General Medicine PP2A 3. Good health Cell biology Cell Transformation Neoplastic Gene Knockdown Techniques embryonic structures Medicine Heterografts Phosphorylation Female Signal Transduction Research Article Human QH301-705.5 Science Phosphatase macromolecular substances Protein Serine-Threonine Kinases Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine Animals Humans Adaptor Proteins Signal Transducing Cell Proliferation 030102 biochemistry & molecular biology General Immunology and Microbiology Cell growth transformation Cancer YAP-Signaling Proteins Protein phosphatase 2 medicine.disease enzymes and coenzymes (carbohydrates) HEK293 Cells 030104 developmental biology Enzyme chemistry Cancer cell Calmodulin-Binding Proteins small t Transcription Factors MAP4K4 |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| ISSN: | 2050-084X |
| Popis: | Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to transformation. Here, we show that ST not only displaces common PP2A B subunits but also promotes A-C subunit interactions with alternative B subunits (B’’’, striatins) that are components of the Striatin-interacting phosphatase and kinase (STRIPAK) complex. We found that STRN4, a member of STRIPAK, is associated with ST and is required for ST-PP2A-induced cell transformation. ST recruitment of STRIPAK facilitates PP2A-mediated dephosphorylation of MAP4K4 and induces cell transformation through the activation of the Hippo pathway effector YAP1. These observations identify an unanticipated role of MAP4K4 in transformation and show that the STRIPAK complex regulates PP2A specificity and activity. eLife digest Cells maintain a fine balance of signals that promote or counter cell growth and division. Two sets of enzymes – called kinases and phosphatases – contribute to this balance. In general, kinases “switch on” other proteins by tagging them with a phosphate molecule. This process is called phosphorylation. Phosphatases, on the other hand, dephosphorylate these proteins, switching them off. Cancer cells often have mutations that activate kinases to drive cancer growth. The same cells can have mutations that inactivate the phosphatases or reduce their abundance. The roles of phosphatases in cancer are still being studied. One major hurdle in this research is that it is not always clear how they recognize the proteins they dephosphorylate. Protein phosphatase 2A (or PP2A for short) is one of the phosphatases that is often mutated or deleted in human cancers. Even just reduced levels of PP2A can promote cancer. Kim, Berrios, Kim, Schade et al. used an experimental trick to decrease the phosphatase activity of PP2A in human cells growing in a dish. Biochemical analysis of these cells showed that, as expected, many proteins were now in their phosphorylated states. Unexpectedly, however, some proteins were dephosphorylated under these conditions. One of these proteins was called MAP4K4. In the case of MAP4K4, the dephosphorylated state contributes to the growth of the cancer cell. Kim et al. carried out further genetic and biochemical experiments to show that, in these cells, PP2A and MAP4K4 stay physically connected to one another. This connection was enabled by a group of proteins called the STRIPAK complex. The STRIPAK proteins directed the remaining PP2A towards MAP4K4. Low levels or activity of PP2A could, therefore, promote cancer in a different way. Taken together, PP2A is not a single phosphatase that always turns proteins off, but rather is a dual switch that turns off some proteins while turning on others. Future experiments will explore to what extent these findings also apply in tumors. Information about how mutations in PP2A affect human cancers could suggest new targets for cancer drugs. |
| Databáze: | OpenAIRE |
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