A NOVEL NEUROENDOCRINE SIGNALING PATHWAY

Expression of many components of the secretory pathway in peptidergic neuroendocrine cells is precisely controlled in response to secretagog ues. Regulated endocrine-specific protein (RESP18) was identified as a dopamine-regulated intermediate pituitary transcript. Although the am ino acid sequence of RESP18 initially suggested that it might be a nov el preprohormone, its widespread expression in peptide-producing neuro ns and endocrine cells and its localization to the lumen of the endopl asmic reticulum suggested that it subserves a unique function. Subtrac tive hybridization of a pituitary corticotrope AtT-20 cell line engine ered for inducible RESP18 expression demonstrated a RESP18-dependent i nduction of several transcripts. Regulation of RESP18 expression in vi tro and in vivo was accompanied by changes in the same transcripts. Se veral cDNAs encoding transcripts up-regulated by RESP18 were analyzed by DNA sequencing, searching the GenBank databases for homologous prot eins, and Northern blotting. One novel clone showed a tissue distribut ion nearly identical to that of RESP18. One clone was identical to rat LIMK2, a protein kinase containing modular protein-protein interactio n LIM (lin-11, isl-1, mec-3) domains. Another clone was similar to mon omeric bacterial isocitrate dehydrogenases. Like the unfolded protein response, these data demonstrate a novel signaling pathway from the se cretory pathway lumen to the nucleus. RESP18 acts as a lumicrine pepti de (an intracellular luminal autocrine hormone) inducing this pathway.