FIGURE 9.

Proposed mechanism by which endosomal ECE-1 regulates SP-stimulated ERK activation and cell death. 1, SP activation of the NK₁R induces receptor phosphorylation by G protein receptor kinases (GRK) and membrane translocation of β-arrestins (β-ARR), which mediate NK₁R desensitization and endocytosis. 2, β-arrestins recruit Src, MEK, and ERK1/2 to form a mitogen-activated protein kinase signaling module in endosomes. 3, ECE-1 degrades SP in acidified endosomes, causing disassembly of the SP-NK₁R-β-arrestin-Src-MEK-ERK1/2 complex. 4, the NK₁R, freed of SP and β-arrestins, recycles to mediate resensitization. 5, sustained ERK2 activation, which occurs in the absence of ECE-1, causes threonine phosphorylation and activation of Nur77, resulting in cell death.