Meta-Biol

• Pathways

Serine (S) 696 in RET is phosphorylated by protein kinase A. Mutation of this serine almost completely inhibits the ability of RET to activate the small GTPase Rac1 and stimulate formation of cell lamellipodia (Fukuda et al. 2002). Homozygous knock-in mice carrying this mutation lacked enteric neurons in the distal colon, resulting from a migration defect of enteric neural crest cells (Asai et al. 2006). The effects of the S696 RET mutant could be alleviated by simultaneous mutation of Tyrosine-687 (Fukuda et al. 2002). Activation of PKA by forskolin was found to impair the recruitment of SHP2 to RET and negatively affect ligand-mediated neurite outgrowth (Perrinjaquet et al. 2010). Mutation of S696 enhanced SHP2 binding and eliminated the effect of forskolin on ligand-induced neurite outgrowth.