title: Role of Lynx1 and related Ly6 proteins as modulators of cholinergic signaling in normal and neoplastic bronchial epithelium.
abstract: The ly-6 proteins are a large family of proteins that resemble the snake three finger alpha toxins such as α-bungarotoxin and are defined by their multiple cysteine residues. Multiple members of the ly-6 protein family can modulate nicotinic signaling including lynx1, lynx2, slurp-1, slurp-2 and prostate stem cell antigen (PSCA). Consistent with the expression of multiple nicotinic receptors in bronchial epithelium, multiple members of the nicotinic-modulatory ly-6 proteins are expressed in lung including lynx1 and lynx2. We studied the role of lynx1 as an exemplar of the role of ly-6 proteins in lung. Our data demonstrates that lynx1 acts as a negative modulator of nicotinic signaling in normal and neoplastic lung. In normal lung lynx1 serves to limit the ability of chronic nicotine exposure to increase levels of nicotinic receptors and also serves to limit the ability of nicotine to upregulate levels of GABAA receptors in lung. In turn this allows lynx1 to limit the ability of nicotine to upregulate levels of mucin which is mediated by GABAergic signaling. This suggests that lynx1-mimetics may have potential for treatment of asthma and COPD. In that most lung cancer cells also express nicotinic receptor and lynx1 we examined the role of lynx-1 in lung cancer. Lynx1 levels are decreased in lung cancers compared to adjacent normal lung. Knockdown of lynx1 by siRNAs increased growth of lung cancer cells while expression of lynx1 in lung cancer cell decreased cell proliferation. This suggests that lynx1 is an endogenous regulator of lung cancer growth. Given that multiple small molecule negative and positive allosteric modulators of nicotinic receptors have already been developed, this suggests that lynx1 is a highly druggable target both for development of drugs that may limit lung cancer growth as well as for drugs that may be effective for asthma or COPD treatment.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
authors.forename: Xiao Wen
authors.initials: XW
authors.lastname: Fu
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
authors.forename: Ping Fang
authors.initials: PF
authors.lastname: Song
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA. Electronic address: spindele@ohsu.edu.
authors.forename: Eliot R
authors.initials: ER
authors.lastname: Spindel
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008253:Macaca mulatta; D018307:Neoplasms, Squamous Cell / Q000378:metabolism*; D059368:RNA Isoforms; D034741:RNA, Small Interfering; D020545:Respiratory Mucosa / Q000166:cytology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000950:Antigens, Ly; D058851:GPI-Linked Proteins; C485626:LYNX1 protein, human; D059368:RNA Isoforms; D034741:RNA, Small Interfering; D000109:Acetylcholine
keywords: Bronchial epithelium; Lung cancer; Ly6; Lynx2; Nicotinic receptor; lynx1