UCSF

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 EGFR^L858R 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.