Substrate-based kinase activity inference identifies MK2 as driver of colitis.

Autor:	Strasser SD; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA., Ghazi PC; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA., Starchenko A; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA., Boukhali M; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.; Center for Cancer Research, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA., Edwards A; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.; Center for Cancer Research, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA., Suarez-Lopez L; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA., Lyons J; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA., Changelian PS; Aclaris Therapeutics, Inc., 4320 Forest Park Avenue, St. Louis, MO 63108, USA., Monahan JB; Aclaris Therapeutics, Inc., 4320 Forest Park Avenue, St. Louis, MO 63108, USA., Jacobsen J; Aclaris Therapeutics, Inc., 4320 Forest Park Avenue, St. Louis, MO 63108, USA., Brubaker DK; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA., Joughin BA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA., Yaffe MB; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA., Haas W; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.; Center for Cancer Research, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA., Lauffenburger DA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA., Haigis KM; Cancer Research Institute and Division of Genetics, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.; Harvard Digestive Disease Center, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115, USA.
Jazyk:	angličtina
Zdroj:	Integrative biology : quantitative biosciences from nano to macro [Integr Biol (Camb)] 2019 Nov 26; Vol. 11 (7), pp. 301-314.
DOI:	10.1093/intbio/zyz025
Abstrakt:	Inflammatory bowel disease (IBD) is a chronic and debilitating disorder that has few treatment options due to a lack of comprehensive understanding of its molecular pathogenesis. We used multiplexed mass spectrometry to collect high-content information on protein phosphorylation in two different mouse models of IBD. Because the biological function of the vast majority of phosphorylation sites remains unknown, we developed Substrate-based Kinase Activity Inference (SKAI), a methodology to infer kinase activity from phosphoproteomic data. This approach draws upon prior knowledge of kinase-substrate interactions to construct custom lists of kinases and their respective substrate sites, termed kinase-substrate sets that employ prior knowledge across organisms. This expansion as much as triples the amount of prior knowledge available. We then used these sets within the Gene Set Enrichment Analysis framework to infer kinase activity based on increased or decreased phosphorylation of its substrates in a dataset. When applied to the phosphoproteomic datasets from the two mouse models, SKAI predicted largely non-overlapping kinase activation profiles. These results suggest that chronic inflammation may arise through activation of largely divergent signaling networks. However, the one kinase inferred to be activated in both mouse models was mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2), a serine/threonine kinase that functions downstream of p38 stress-activated mitogen-activated protein kinase. Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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