Guo, Hou-FuBota-Rabassedas, NeusTerajima, MasahikoLeticia Rodriguez, B.Gibbons, Don L.Chen, YulongBanerjee, PriyamTsai, Chi-LinTan, XiaochaoLiu, XinYu, JiangTokmina-Roszyk, MichalStawikowska, RomaFields, Gregg B.Miller, Mitchell D.Wang, XiaoyanLee, JuhoonDalby, Kevin N.Creighton, Chad J.Phillips, George N.Jr.Tainer, John A.Yamauchi, MitsuoKurie, Jonathan M.2021-06-072021-06-072021Guo, Hou-Fu, Bota-Rabassedas, Neus, Terajima, Masahiko, et al.. "A collagen glucosyltransferase drives lung adenocarcinoma progression in mice." <i>Communications Biology,</i> 4, (2021) Springer Nature: https://doi.org/10.1038/s42003-021-01982-w.https://hdl.handle.net/1911/110696Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen’s amino- and carboxy-terminal telopeptides to create stable collagen cross-links. Here, we show that electrostatic interactions between the LH domain active site and collagen determine the unique telopeptidyl lysyl hydroxylase (tLH) activity of LH2. However, CRISPR/Cas-9-mediated inactivation of tLH activity does not fully recapitulate the inhibitory effect of LH2 knock out on LUAD growth and metastasis in mice, suggesting that LH2 drives LUAD progression, in part, through a tLH-independent mechanism. Protein homology modeling and biochemical studies identify an LH2 isoform (LH2b) that has previously undetected collagen galactosylhydroxylysyl glucosyltransferase (GGT) activity determined by a loop that enhances UDP-glucose-binding in the GLT active site and is encoded by alternatively spliced exon 13 A. CRISPR/Cas-9-mediated deletion of exon 13 A sharply reduces the growth and metastasis of LH2b-expressing LUADs in mice. These findings identify a previously unrecognized collagen GGT activity that drives LUAD progression.engThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.Journal articles42003-021-01982-whttps://doi.org/10.1038/s42003-021-01982-w