title: A new role for Hedgehogs in juxtacrine signaling.
abstract: The Hedgehog pathway plays important roles in embryonic development, adult stem cell maintenance and tumorigenesis. In mammals these effects are mediated by Sonic, Desert and Indian Hedgehog (Shh, Dhh and Ihh). Shh undergoes autocatalytic cleavage and dual lipidation prior to secretion and forming a response gradient. Post-translational processing and secretion of Dhh and Ihh ligands has not previously been investigated. This study reports on the synthesis, processing, secretion and signaling activities of SHH, IHH and DHH preproteins expressed in cultured cells, providing unexpected evidence that DHH does not undergo substantial autoprocessing or secretion, and does not function in paracrine signaling. Rather, DHH functions as a juxtacrine signaling ligand to activate a cell contact-mediated HH signaling response, consistent with its localised signaling in vivo. Further, the LnCAP prostate cancer cell, when induced to express endogenous DHH and SHH, is active only in juxtacrine signaling. Domain swap studies reveal that the C-terminal domain of HH regulates its processing and secretion. These findings establish a new regulatory role for HHs in cell-mediated juxtacrine signaling in development and cancer.
authors.affiliation: Boston Biomedical Research Institute, 64 Grove Street, Watertown, 02472 MA, USA; University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655 MA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Pettigrew
authors.affiliation: Boston Biomedical Research Institute, 64 Grove Street, Watertown, 02472 MA, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Asp
authors.affiliation: Boston Biomedical Research Institute, 64 Grove Street, Watertown, 02472 MA, USA; University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655 MA, USA. Electronic address: Charles.Emersonjr@umassmed.edu.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Emerson
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D019899:Paracrine Communication; D011247:Pregnancy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000235:genetics
chemical_list: C509245:DHH protein, human; D053823:Hedgehog Proteins; C509246:IHH protein, human; C509239:SHH protein, human
keywords: Development; Hedgehog; Processing; Secretion; Signaling