Sprouty and Spred as Inhibitors of the RAS-ERK Pathway
The Ras-ERK pathway critically regulates several cellular processes including survival, growth and differentiation, and is often deregulated in diseases such as cancer. Two protein families, Sprouty (Spry) and Spred (Sprouty-related protein with EVH1 domain), function as intracellular inhibitors of this pathway downstream of receptor tyrosine kinases (RTKs). Members of both families have been found to be downregulated in various cancers, with their decreased expression correlating with cell transformation, migration and metastasis. Spry and Spred share similarity across a highly-conserved Cys-rich C-terminus, though its role in their ERK inhibitory function remains controversial. In this study, testicular protein kinase 1 (Tesk1) was identified as a common interacting partner to Spry and Spred that binds through this region. Tesk1 coexpression relocalizes Spry2 and Spred1 to vesicles including endosomes, leading to inhibition of their translocation to membrane ruffles upon growth factor stimulation. However, this has different effects on the cellular functions of Spry2 and Spred1. Interaction with Tesk1 abolishes the ERK inhibitory capacity of Spry2 downstream of fibroblast growth factor receptor (FGFR) stimulation while not affecting its regulation of epidermal growth factor receptor (EGFR) ubiquitination. Conversely, Tesk1 binding does not affect ERK inhibition by Spred1. Detailed analysis of the molecular basis for these differences was carried out, and the results highlight the distinct modes of action employed by Spry and Spred in inhibiting RTK signaling.
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