TRUNCATED, DESENSITIZATION-DEFECTIVE NEUROKININ RECEPTORS MEDIATE SUSTAINED MAP KINASE ACTIVATION, CELL-GROWTH AND TRANSFORMATION BY A RAS-INDEPENDENT MECHANISM

We have used the neurokinin NK-2 receptor as a model to examine how re ceptor desensitization affects cellular responses. The liganded recept or transiently activates phospholipase C (PLC) and is rapidly phosphor ylated on Ser/Thr residues in its C-terminal domain. Mutant receptors lacking this domain mediate persistent activation of PLC. We now show that, in transfected Rat-1 cells, mutant receptor mediates ligand-indu ced DNA synthesis, morphological transformation and growth in soft aga r, whereas wild-type (wt) receptor does not. Wt receptor causes only t ransient MAP kinase activation. In contrast, MAP kinase activation by mutant receptor is sustained for >4 h. Neither wt nor mutant receptor couples to Ras activation. Downregulation of protein kinase C (PKC) ha s little effect on MAP kinase activation, DNA synthesis and transforma tion. Mutant receptors also promote stronger protein tyrosine phosphor ylation and stress fibre formation than does wt receptor. Thus, C-term inal truncation allows the NK-2 receptor to signal sustained MAP kinas e activation, cell growth and transformation by a Ras- and PKC-indepen dent mechanism. Our results reveal the importance of the C-terminal 'd esensitization domain' in suppressing the oncogenic potential of a pro totypic PLC-coupled receptor.