A novel neuroendocrine intracellular signaling pathway.
Expression of many components of the secretory pathway in peptidergic neuroendocrine cells is precisely controlled in response to secretagogues. Regulated endocrine-specific protein (RESP18) was identified as a dopamine-regulated intermediate pituitary transcript. Although the amino acid sequence of RESP18 initially suggested that it might be a novel preprohormone, its widespread expression in peptide-producing neurons and endocrine cells and its localization to the lumen of the endoplasmic reticulum suggested that it subserves a unique function. Subtractive hybridization of a pituitary corticotrope AtT-20 cell line engineered for inducible RESP18 expression demonstrated a RESP18-dependent induction of several transcripts. Regulation of RESP18 expression in vitro and in vivo was accompanied by changes in the same transcripts. Several cDNAs encoding transcripts up-regulated by RESP18 were analyzed by DNA sequencing, searching the GenBank databases for homologous proteins, and Northern blotting. One novel clone showed a tissue distribution nearly identical to that of RESP18. One clone was identical to rat LIMK2, a protein kinase containing modular protein-protein interaction LIM (lin-11, isl-1, mec-3) domains. Another clone was similar to monomeric bacterial isocitrate dehydrogenases. Like the unfolded protein response, these data demonstrate a novel signaling pathway from the secretory pathway lumen to the nucleus. RESP18 acts as a lumicrine peptide (an intracellular luminal autocrine hormone) inducing this pathway.
Schiller
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MR
The Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2105, USA.
Mains
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Eipper
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D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015259:Dopamine Agents / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry; D009490:Neurosecretory Systems; D009693:Nucleic Acid Hybridization; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic / Q000187:drug effects
D015259:Dopamine Agents; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C086381:regulated endocrine secretory protein 18; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase