Intestinal cell kinase (ICK) localizes to the crypt region and requires a dual phosphorylation site found in map kinases

Togawa, Kazumi; Yan, Yizhou; Inomoto, Takuya; Slaugenhaupt, Susan; Rustgi, Anil K.

doi:10.1002/(sici)1097-4652(200004)183:1<129::aid-jcp15>3.0.co;2-s

Cited by 49 publications

(59 citation statements)

References 20 publications

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“…Thus, the b-catenin signal in conjunction with p21-mediated G1-arrest is both necessary and sufficient for induction of intestinal-specific molecules in gastric epithelial cells. Consistently, DNA microarray analysis revealed that CagA also upregulates intestinal-specific genes such as intestinal cell kinase and an intestine crypt transcription factor SOX9 (Table 1) (Togawa et al, 2000;Blache et al, 2004). Among genes transcriptionally upregulated by CagA, those that unchanged by serum starvation are picked up.…”

Section: Induction Of Intestinal Transdifferentiation In Gastric Epitmentioning

confidence: 65%

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and b-catenin, causing cytoplasmic and nuclear accumulation of b-catenin. CagA-deregulated b-catenin then transactivates b-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to b-catenin signal, CagA also transactivates p21 WAF1/Cip1 , again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21 WAF1/Cip1 . These results indicate that perturbation of the E-cadherin/b-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.

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Section: Induction Of Intestinal Transdifferentiation In Gastric Epitmentioning

confidence: 65%

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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“…Interestingly, we could not find an obvious homologue in Plasmodium, which has cilia, but the cilia are assembled in the cytoplasm in a process that does not require IFT (42). Mammals have three putative DYF-5 homologues that form a small subfamily of MAP kinases, the MAK kinases (22)(23)(24)(25). The functions of these MAK, MOK, and ICK/MRK proteins remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…dyf-5 encodes a protein of 471 aa, which shows extensive homology to three mammalian proteins that form a small subfamily of MAP kinases. This subfamily consists of MAK (male germ cell-associated kinase) (22), ICK or MRK (intestinal cell kinase and MAKrelated kinase, respectively) (23,24), and MOK (MAPK/MAK/ MRK overlapping kinase) (25), with highly conserved N-terminal catalytic domains and more divergent C-terminal noncatalytic domains. Although the functions of these kinases in mammals are not known, studies in other organisms suggest a function in the cilia.…”

mentioning

confidence: 86%

Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans

Burghoorn¹,

Dekkers²,

Rademakers³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

116

178

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In the cilia of the nematode Caenorhabditis elegans, anterograde intraflagellar transport (IFT) is mediated by two kinesin-2 complexes, kinesin II and OSM-3 kinesin. These complexes function together in the cilia middle segments, whereas OSM-3 alone mediates transport in the distal segments. Not much is known about the mechanisms that compartmentalize the kinesin-2 complexes or how transport by both kinesins is coordinated. Here, we identify DYF-5, a conserved MAP kinase that plays a role in these processes. Fluorescence microscopy and EM revealed that the cilia of dyf-5 loss-of-function (lf) animals are elongated and are not properly aligned into the amphid channel. Some cilia do enter the amphid channel, but the distal ends of these cilia show accumulation of proteins. Consistent with these observations, we found that six IFT proteins accumulate in the cilia of dyf-5(lf) mutants. In addition, using genetic analyses and live imaging to measure the motility of IFT proteins, we show that dyf-5 is required to restrict kinesin II to the cilia middle segments. Finally, we show that, in dyf-5(lf) mutants, OSM-3 moves at a reduced speed and is not attached to IFT particles. We propose that DYF-5 plays a role in the undocking of kinesin II from IFT particles and in the docking of OSM-3 onto IFT particles.cilia length ͉ dyf-5 ͉ intraflagellar transport C ilia are present on almost every vertebrate cell and have important functions in motility or sensation. Within cilia, structural components and signaling molecules are transported by a specialized system, called intraflagellar transport (IFT) (1-5). Transport from the base of the cilia to the tip (anterograde) is mediated by kinesin-2 motor complexes, whereas dynein motor complexes mediate transport back to the base (retrograde). The nematode Caenorhabditis elegans has 60 ciliated neurons, including eight pairs of amphid neurons exposed to the environment (6). The cilia of these neurons can be divided into a middle segment with nine doublet microtubules and a distal segment with nine singlet microtubules (7). In the middle segments, two distinct kinesin-2 motor complexes mediate anterograde transport, heterotrimeric kinesin II, encoded by klp-11, klp-20, and kap-1 and homodimeric OSM-3 kinesin (8). In the distal segments, transport is mediated by only OSM-3 (8). Live imaging of the movement of these kinesins suggests that kinesin II alone moves at 0.5 m/s, and OSM-3 alone moves at 1.3 m/s, whereas the two motor complexes together move at 0.7 m/s (8). Recently, Pan et al. (9) have shown that these in vivo transport rates can be reconstituted in vitro by using purified kinesin II and OSM-3 motors. Thus far, two proteins have been identified that are required to stabilize IFT complexes transported by both kinesin II and OSM-3, BBS-7 and BBS-8 (10). However, it remains unclear how kinesin II is restricted to the cilia middle segments, whereas OSM-3 is allowed to enter the distal segments and what the functional significance is of this compartmentalization.Recently, Evans e...

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“…ICK, which is highly expressed in intestinal crypt epithelium, shares sequence similarity with mitogen-activated protein kinase (MAPK) family proteins (2). The catalytic activity of ICK is regulated by dual phosphorylation of a MAPK-like TDY motif in the activation T loop as well as the phosphorylation of Thr residues in the TDY motif by cell-cycle-related kinase (CCRK) (3).…”

mentioning

confidence: 99%

Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling

Moon

Song

Shin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

115

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Endocrine-cerebro-osteodysplasia (ECO) syndrome is a recessive genetic disorder associated with multiple congenital defects in endocrine, cerebral, and skeletal systems that is caused by a missense mutation in the mitogen-activated protein kinase-like intestinal cell kinase (ICK) gene. In algae and invertebrates, ICK homologs are involved in flagellar formation and ciliogenesis, respectively. However, it is not clear whether this role of ICK is conserved in mammals and how a lack of functional ICK results in the characteristic phenotypes of human ECO syndrome. Here, we generated Ick knockout mice to elucidate the precise role of ICK in mammalian development and to examine the pathological mechanisms of ECO syndrome. Ick null mouse embryos displayed cleft palate, hydrocephalus, polydactyly, and delayed skeletal development, closely resembling ECO syndrome phenotypes. In cultured cells, down-regulation of Ick or overexpression of kinase-dead or ECO syndrome mutant ICK resulted in an elongation of primary cilia and abnormal Sonic hedgehog (Shh) signaling. Wild-type ICK proteins were generally localized in the proximal region of cilia near the basal bodies, whereas kinase-dead ICK mutant proteins accumulated in the distal part of bulged ciliary tips. Consistent with these observations in cultured cells, Ick knockout mouse embryos displayed elongated cilia and reduced Shh signaling during limb digit patterning. Taken together, these results indicate that ICK plays a crucial role in controlling ciliary length and that ciliary defects caused by a lack of functional ICK leads to abnormal Shh signaling, resulting in congenital disorders such as ECO syndrome.

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Intestinal cell kinase (ICK) localizes to the crypt region and requires a dual phosphorylation site found in map kinases

Cited by 49 publications

References 20 publications

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans

Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling

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