CSIG-37. MERLIN S13 DEPHOSPHORYLATION DRIVES MENINGIOMA WNT SIGNALLING AND CELL PROLIFERATION
نویسندگان
چکیده
Abstract How Merlin-intact meningiomas arise in the absence of NF2/Merlin inactivation is incompletely understood. Here, we integrate single-cell RNA sequencing 86,000 cells from meningioma xenografts with APEX2 proteomic proximity-labelling mass spectrometry and functional biochemical approaches to discover Merlin Serine 13 (S13) dephosphorylation drives Wnt signalling cell proliferation. Cell biology, molecular techniques were used validate functions or using wildtype constructs encoding S13A, phosphomimetic S13D, cancer-associated missense substitutions (L46R, A211D). Single-cell showed rescue activated pathway Merlin-deficient meningiomas. Proteomic revealed b-catenin, PKC, PP1A interactions Merlin, but not L46R A211D. b-catenin does interact other FERM family members, contains a unique N-terminal domain (NTD) PKC phosphorylation motif overlapping at S13. Thus, hypothesized S13, may be important for In support this hypothesis, over-expression S13A DNTD, L46R, A211D, members drove sustained proliferation vivo. Moreover, was detected proximity S13D cells. Meningioma fractionation immunofluorescence stabilized plasma membrane inhibited signalling. Phospho-proteomic custom phospho-specific antibodies integrated shRNA siRNA gene suppression demonstrated phosphorylated activation induced dephosphorylate S13 drive summary, These data reveal novel tumor-promoting function
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2022
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noac209.186