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.

Ciliogenesis associated kinase 1: targets and functions in various organ systems

“…This phenomenon is reminiscent of what we observed in the intestinal epithelium where CILK1 expression can be induced under nutritional stress [36] or radiation injury (unpublished data). Conditional KO mouse models will be needed to interrogate the role of CILK1 in the heart under both normal and pathophysiological conditions.…”

Protein Malnutrition Impairs Intestinal Epithelial Cell Turnover, a Potential Mechanism of Increased Cryptosporidiosis in a Murine Model

“…As changes in major signaling pathways that govern intestinal cellular response to stress were found in our previous work to occur mostly at 24 h after challenge, we modified our model with weaned mice and gave them the double challenge of a protein-deficient diet and C. parvum infection at the same time, and then examined the early changes at days 1 and 3 postinfection (15). We successfully reproduced the intensified C.…”

“…Its antiapoptotic role in intestinal epithelial cells of murine models has been shown in many studies (23, 24, 39). Our previous study demonstrated that the small intestine responds to protein malnutrition by activating major survival pathways and entering a “survival mode” (15). Activation of Akt pathways was found in our previous study and the present study, which may play a role in increasing cellular resistance to apoptosis.…”

“…In a previous study, we demonstrated that even very brief periods (<24 h) of protein malnutrition cause rapid activation of intestinal cell kinase (ICK) as well as the Akt pathway in intestinal epithelial cells (15). In the present study, in order to determine whether these rapid intestinal cell signaling changes caused by protein malnutrition impact susceptibility to Cryptosporidium infection, we used a modified model of weaned mice challenged with C.…”

An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome

“…ICK is very similar to MAP kinase in the catalytic domain and contains a MAPK-like TDY motif in its activation loop [3, 4]. By knocking down ICK expression using short-hairpin RNA interference, our work has demonstrated an important role for ICK in the regulation of cell proliferation and survival in vitro [5, 6]. An essential role of ICK in human development emerged from the report of human ECO and ECO-like syndromes whose major clinical features include hydrocephalus, polydactyly and micromelia [1, 7, 8].…”