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Oncogene-mediated inhibition of the Spred1 tumor suppressor

  • Author(s): Markegard, Evan Curtis
  • Advisor(s): McCormick, Frank
  • et al.

Spred proteins are tumor suppressors which negatively regulate Ras/MAPK signaling following growth factor stimulation. Inhibition of Ras is thought to primarily occur through the ability of Spred1 to bind and localize Neurofibromin (NF1), a RasGAP, to the plasma membrane. SPRED1 and NF1 loss-of-function mutations tend to be mutually exclusive and occur across multiple cancer types and developmental diseases. We show oncogenic EGFRL858R signaling leads to the phosphorylation of Spred1 on serine 105 which disrupts the Spred1-Neurofibromin complex. The primary Spred1(S105) kinase was identified as CDK1. Spred1 directly binds CDK1 and enters the nucleus though a newly identified Class I nuclear localization sequence. Additionally, phosphomimetic Spred1 is unable to suppress Ras-GTP following growth factor stimulation and proliferation in the K562 leukemia cell line. Our findings provide one potential mechanism by which oncogenic signaling disrupts Spred1-Neurofibromin negative feedback of the Ras/MAPK pathway.

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