A comparative study of Sprouty and Spred as inhibitors of the RAS-ERK pathway

Abstract

<P>SPROUTY (SPRY) AND SPRED (SPROUTY-RELATED PROTEIN WITH EVH1 DOMAIN) PROTEINS FUNCTION AS INTRACELLULAR INHIBITORS OF THE RAS-ERK PATHWAY DOWNSTREAM OF RECEPTOR TYROSINE KINASES (RTKS) AND SHARE SIMILARITY ACROSS A HIGHLY-CONSERVED CYS-RICH C-TERMINUS. IN THIS STUDY, TESTICULAR PROTEIN KINASE 1 (TESK1) WAS ISOLATED AS A COMMON INTERACTING PARTNER TO BOTH PROTEIN FAMILIES THAT BINDS THROUGH THIS REGION. TESK1 CO-EXPRESSION RE-LOCALIZES SPRY2 AND SPRED1 TO VESICLES INCLUDING ENDOSOMES, LEADING TO INHIBITION OF THEIR TRANSLOCATION TO MEMBRANE RUFFLES UPON GROWTH FACTOR STIMULATION. HOWEVER, THIS INTERACTION HAS DIFFERENT EFFECTS ON THE CELLULAR FUNCTIONS OF SPRY2 AND SPRED1. TESK1 BINDING 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, HIGHLIGHTING THE DIFFERENCE