title: Intestinal cell kinase is a novel participant in intestinal cell signaling responses to protein malnutrition.
abstract: Nutritional deficiency and stress can severely impair intestinal architecture, integrity and host immune defense, leading to increased susceptibility to infection and cancer. Although the intestine has an inherent capability to adapt to environmental stress, the molecular mechanisms by which the intestine senses and responds to malnutrition are not completely understood. We hereby report that intestinal cell kinase (ICK), a highly conserved serine/threonine protein kinase, is a novel component of the adaptive cell signaling responses to protein malnutrition in murine small intestine. Using an experimental mouse model, we demonstrated that intestinal ICK protein level was markedly and transiently elevated upon protein deprivation, concomitant with activation of prominent pro-proliferation and pro-survival pathways of Wnt/β-catenin, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and protein kinase B (PKB/Akt) as well as increased expression of intestinal stem cell markers. Using the human ileocecal epithelial cell line HCT-8 as an in vitro model, we further demonstrated that serum starvation was able to induce up-regulation of ICK protein in intestinal epithelial cells in a reversible manner, and that serum albumin partially contributed to this effect. Knockdown of ICK expression in HCT-8 cells significantly impaired cell proliferation and down-regulated active β-catenin signal. Furthermore, reduced ICK expression in HCT-8 cells induced apoptosis through a caspase-dependent mechanism. Taken together, our findings suggest that increased ICK expression/activity in response to protein deprivation likely provides a novel protective mechanism to limit apoptosis and support compensatory mucosal growth under nutritional stress.
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: David T
authors.initials: DT
authors.lastname: Bolick
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America; Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong, China.
authors.forename: Tufeng
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Luís Antonio O
authors.initials: LA
authors.lastname: Alves
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America; Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science & Technology, Hubei, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Linwood T
authors.initials: LT
authors.lastname: Joyner
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Reinaldo B
authors.initials: RB
authors.lastname: Oriá
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
authors.affiliation: Department of Medicine, Center for Global Health, Digestive Research Center of Excellence, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D011488:Protein Deficiency / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C097276:CILK1 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C000591805:Cilk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases