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R‐Ras Subfamily Proteins Elicit Distinct Physiologic Effects and Phosphoproteome Alterations in Neurofibromin‐Null MPNST Cells
Author(s) -
Prechtl Amanda,
Brossier Nicole,
Barnes Stephen,
Wilson Landon,
Brosius Stephanie,
Byer Stephanie,
Carroll Steven
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1179.8
Subject(s) - neurofibromin 1 , biology , gtpase , neurofibromatosis , gene knockdown , cancer research , carcinogenesis , microbiology and biotechnology , subfamily , gtpase activating protein , mediator , signal transduction , cell culture , genetics , g protein , gene
Loss of the Ras GTPase‐activating protein neurofibromin promotes the development of multiple nervous system tumors in patients with the genetic disorder neurofibromatosis type 1 (NF1). Neurofibromin loss potentially results in the activation of both classic Ras (H‐Ras, N‐Ras, K‐Ras) and R‐Ras (R‐Ras, R‐Ras2/TC21, R‐Ras3/M‐Ras) subfamily proteins. Previously, we have shown that the classic Ras family inhibit neurofibromin‐null malignant peripheral nerve sheath tumor (MPNST) cell mitogenesis. In order to determine whether the R‐Ras proteins differentially contribute to the pathogenesis of neurofibromin‐null MPNST cells, we inhibited the R‐Ras family proteins and assessed the impact of R‐Ras inhibition on mitogenesis, survival, migration and the phosphoproteome. We show that R‐Ras and R‐Ras2 are expressed and can be activated in neurofibromin‐null MPNST cells. Additionally, like DN H‐Ras, DN R‐Ras inhibits MPNST mitogenesis, however only DN R‐Ras inhibits migration. These findings were further validated by individual shRNA knockdown of the R‐Ras proteins. Using mass spectrometry‐based phosphoproteomics, we found that DN R‐Ras regulated thirteen largely distinct networks, one of which regulates cellular movement via effects on microtubules. We conclude that like classic Ras proteins, R‐Ras proteins can promote tumorigenesis, albeit via different effects that involve the activation of distinct signaling pathways.