Fig. 9.

Model of RIN1 action in RAS-mediated pathways controlling learning and memory. Neurotransmitter receptor stimulation leads to activation of RAS exchange factors (SOS, GRF, RasGRP, and cnRAS-GEF) in postsynaptic cells. Negative regulators of RAS in neurons include the GTPase-activating proteins NF1 and SynGAP. RAS proteins signal through RAF proteins to initiate the MAP kinase cascade, resulting in transcription changes required for long-term memory. RIN1 inhibits this pathway by competing with RAF (and probably other RAS effectors, such as PI3K and RalGDS) for the effector binding site on RAS. RIN1 functions through two downstream pathways: (1) activation of RAB5 to promote receptor endocytosis and downregulation and (2) activation of ABL1 and ABL2 tyrosine kinases, leading to cytoskeletal remodeling involved in structural changes that may diminish synaptic strength of excitatory cells.