Nutritional deficiency and stress can severely impair intestinal architecture integrity and host immune defense leading to increased susceptibility to infection and cancer. of prominent pro-proliferation Batimastat (BB-94) 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. Batimastat (BB-94) Using the human ileocecal epithelial cell line HCT-8 as an 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 Batimastat (BB-94) 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. Introduction Intestinal luminal nutrients constitute the primary stimulus for intestinal growth. Intra-lumen food is with the capacity of stimulating gut mucosal development either straight through local impact at the website of absorption or indirectly by regulating the discharge of gut human hormones that are essential for mucosal development and restoration [1] [2]. Hunger can trigger mucosal atrophy in the tiny intestine seen as a diminished intestinal features aswell as modified morphological constructions including reduced villous elevation crypt depth surface and epithelial cell amounts [3] [4]. In response to a nutritional challenge the tiny intestine exhibits an extraordinary capability of mucosal version to avoid atrophy and keep maintaining normal mucosal structures and functions. Nevertheless very little is well known about the molecular basis root the intestinal mobile responses to dietary stress. Main signaling Batimastat (BB-94) pathways such as for example Wnt/β-catenin [5] PI3K/Akt [6] mTOR/S6K1 [7] and MAPKs [8] govern intestinal cell development differentiation migration and success in the intestinal mucosa. An interesting question that has not been fully addressed is whether and how these crucial signaling cascades respond to nutritional deficiency. Intestinal cell kinase (ICK) is a newly emerged key component in the intestinal cell signaling network [9] [10]. ICK named after its cloning origin the intestine is an evolutionarily conserved serine/threonine protein kinase in the protein kinome that is closely related to mitogen-activated protein kinases (MAPKs). In the small intestine ICK mRNA specifically localizes to the crypt region where intestinal stem/progenitor cells and the rapidly replicating transit-amplifying cells reside implicating an important role for ICK in the regulation of epithelial cell replication and stem cell activities [9]. To support this hypothesis we LRRC48 antibody have shown that knockdown of ICK expression is able to significantly impair intestinal epithelial cell proliferation [10]. Murine ICK gene encodes a protein of 629 amino acid residues comprised of a highly conserved N-terminal catalytic domain and a unique long C-terminal domain [11] [12]. ICK can be activated Batimastat (BB-94) by an upstream kinase CCRK (cell cycle-related kinase) through phosphorylation of the essential Thr-157 residue in its MAPK-like TDY motif [11]. The signaling axis of CCRK-ICK plays an important role in the regulation of cell cycle progression at G1 [10] [13] [14]. However unlike MAPKs ICK activity was not acutely stimulated by serum or growth factors [9]. It remains a major question as to what upstream stimuli or environmental cues that may regulate ICK expression and/or activity. The physiologic functions and substrates of ICK in the intestine are still elusive. We hereby report that nutritional stress as an environmental cue is capable of acutely and transiently regulating ICK protein/activity level. By knocking down ICK expression using lentiviral short-hairpin RNA interference (shRNA) we demonstrated that ICK signaling is important for intestinal cell proliferation and survival through β-catenin-mediated and caspase-dependent pathways respectively. These results claim that intestinal epithelial cells may up-regulate ICK signaling pathway like a protecting system to limit apoptosis and promote compensatory development during intestinal.