Precursor structure, expression, and tissue distribution of human guanylin.
Heat-stable enterotoxins (STa) are small, cysteine-rich peptides secreted by Escherichia coli that are able to induce diarrhea through the stimulation of an intestine-specific receptor-guanylyl cyclase known as STaR. A 15-amino acid peptide, guanylin, was recently purified from rat jejunum and proposed to be a potential endogenous activator of this receptor. We describe here the cloning and characterization of human and mouse cDNAs encoding precursor proteins of 115 and 116 amino acids, respectively, having guanylin present at their C termini. Expression of the human cDNA in mammalian cells leads to the secretion of proguanylin, an inactive 94-amino acid protein. Guanylin generated by either trypsin or acid treatment of proguanylin was purified and found to bind to, and activate, STaR. Northern blot and in situ hybridization show high-level expression of guanylin mRNA restricted to the intestine, with localization to Paneth cells at the base of the small intestinal crypts. These results demonstrate that guanylin is an endogenous activator of STaR.
de Sauvage
F J
FJ
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
Keshav
S
S
Kuang
W J
WJ
Gillett
N
N
Henzel
W
W
Goeddel
D V
DV
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005768:Gastrointestinal Hormones; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D007421:Intestine, Small / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D045265:Natriuretic Peptides; D015345:Oligonucleotide Probes; D009928:Organ Specificity; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D015345:Oligonucleotide Probes; D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; C072685:guanylin; D004247:DNA