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Kim, Hangun,Han, Jeong-Ran,Park, Jaejun,Oh, Minsoo,James, Sarah E,Chang, Sunghoe,Lu, Qun,Lee, Kwang Youl,Ki, Hyunkyoung,Song, Woo-Joo,Kim, Kwonseop American Society for Biochemistry and Molecular Bi 2008 The Journal of biological chemistry Vol.283 No.2
<P>Delta-catenin was first identified through its interaction with Presenilin-1 and has been implicated in the regulation of dendrogenesis and cognitive function. However, the molecular mechanisms by which delta-catenin promotes dendritic morphogenesis were unclear. In this study, we demonstrated delta-catenin interaction with p190RhoGEF, and the importance of Akt1-mediated phosphorylation at Thr-454 residue of delta-catenin in this interaction. We have also found that delta-catenin overexpression decreased the binding between p190RhoGEF and RhoA, and significantly lowered the levels of GTP-RhoA but not those of GTP-Rac1 and -Cdc42. Delta-catenin T454A, a defective form in p190RhoGEF binding, did not decrease the binding between p190RhoGEF and RhoA. Delta-catenin T454A also did not lower GTP-RhoA levels and failed to induce dendrite-like process formation in NIH 3T3 fibroblasts. Furthermore, delta-catenin T454A significantly reduced the length and number of mature mushroom shaped spines in primary hippocampal neurons. These results highlight signaling events in the regulation of delta-catenin-induced dendrogenesis and spine morphogenesis.</P>
DIRECT EVIDENCE FOR A ROLE OF β-CATENIN/LEF-1 SIGNALING PATHWAY IN INDUCTION OF EMT
KIM, KWONSEOP,LU, ZIFAN,HAY, ELIZABETH D. 전남대학교 약품개발연구소 2002 약품개발연구지 Vol.11 No.-
Epithelial-mesenchymal transformation (EMT) is an important process in development that is characterized by loss of E-cadherin, β-catenin relocalization, and acquisition of elongated cell shape and ability to invade ECM. β-catenin has been shown to activate LEF-1 transcription during EMT induced in vitro by c-Fos. Here, we ask whether or not LEF-1 directly introduced into epithelial cells in an adenovirus construct can in duce EMT. In normal epithelial cell lines, such as HCE and MDSK cells, that contain functional APC, nuclear β-catenin induced by exogenous LEF-1 is rapidly exported and EMT is not induced. Leptomycin-B blocks β-catenin nuclear export, but no EMT occurs due to toxicity. Addition of Wnt-1 to normal epithelial cell lines stabilizes cytoplasmic β-catenin that LEF-1 then transports to nuclei, causing a small amount of EMT. Our experiments demonstrated, however, that overexpressed LEF-1 upregulates nuclear β-catenin and promotes dramatic EMT in DLD-1 epithelial tumors that retain nuclear β-catenin. This EMT is reversible if the LEF-1 virus is removed. Thus, our results demonstrate that LEF-1 can induce EMT directly when its transcription activity is activated by stable nuclear β-catenin. Normal epithelial cells appear to use APC to keep β-cathnin out of the nucleus, thereby avoiding pathologies such as metastases due to LEF/β-catenin-induced EMT.
Kim, KWONSEOP,Lee, Kwang-Youl 전남대학교 약품개발연구소 2001 약품개발연구지 Vol.10 No.-
β-catenin plays an essential role in cells, not only as a cadherin-associated complex, but also as a signaling molecule in the nucleus. Tyrosine phosphorylation of β-catenin has been shown to correlate with tumorigenesis, cell migration, and developmental processes. However, its exact effects on downstream targets in the nucleus are not yet clear. In this study, we used HCT-15 colon carcinoma and NIH 3T3 fibroblasts as models to investigate the effects of a phosphotyrosine phosphatase (PTPase) inhibitor on the localization of β-catenin, the binding affinity to LEF-1 (Lymphoid Enhancer Factor), and on LEF-1-dependent transactivation function. Treatment with a PTPase inhibitor, pervanadate, increased the tyrosine phosphorylation of β-catenin in a time-dependent manner and led to its relocation from cell-cell interfaces to the cytoplasm. This phosphorylation/dephosphorylation of β-catenin does not require its presence at cell-cell interfaces. However, tyrosine phosphorylation of β-catenin does not change its binding affinity to LEF-l nor enhance cyclin D1 transactivation, a nuclear target of β-catenin/ LEF-l. This result suggests that tyrosine phosphorylation of β-catenin has effects on the binding to cadherins in the cytoplasm but not on its LEF-l-dependent transactivating function in the nucleus.
Kim, Hangun,Ki, Hyunkyoung,Park, Hee-Sae,Kim, Kwonseop American Society for Biochemistry and Molecular Bi 2005 The Journal of biological chemistry Vol.280 No.23
<P>The enzyme γ-secretase is involved in the cleavage of several type I membrane proteins, such as Notch 1 and amyloid precursor protein. Presenilin-1 (PS-1) is one of the critical integral membrane protein components of the γ-secretase complex and is processed endoproteolytically, generating N- and C-terminal fragments (NTF and CTF, respectively). PS-1 is also known to incorporate into a high molecular weight complex by binding to other γ-secretase components such as Nicastrin, Aph-1, and Pen-2. Mutations on PS-1 can alter the effects of γ-secretase on its many substrates to different extents. Here, we showed that PS-1 mutants have a different activity for Notch cleavage, which depended on the PS-1 mutation site. We demonstrated that defective PS-1 mutants located in CTF, <I>i.e.</I> D385A and C410Y, could restore their γ-secretase activities with the compensatory overexpression of wild type CTF or of minimal deleted CTF (amino acids 349-467). However, the defective PS-1 D257A mutant could not restore their γ-secretase activities with the compensatory overexpression of wild type NTF. In comparison, both D257A NTF and D385A CTF could abolish the γ-secretase activity of wild type and pathogenic PS-1 mutants. We also showed that PS-1 NTF but not CTF forms strong high molecular weight aggregates in SDS-PAGE. Taken together, results have shown that NTF and CTF integrate differently into high molecular weight aggregates and that PS-1 Asp-257 and Asp-385 have different accessibilities in their unendoproteolyzed conformation.</P>
Kim, KWONSEOP,Elizabeth D. Hay 전남대학교 약품개발연구소 2001 약품개발연구지 Vol.10 No.-
The once accepted idea that LEF- 1 transports β-catenin into nuclei has recently been challenged by experiments using exogenous β-catenin. Here, we investigated the effects of β-catenin and LEF-1 on nuclear import of β-catenin using different combinations of exogenous and endogenous molecules over longer lengths of time than previously studied. Nuclear β-catenin is not detectable in corneal fibroblasts and epithelia or NIH 3T3 and MDCK cells. In LEF-1 transfections, we show that the B-box of LEF-1 is required to move cytoplasmic endogenous β-catenin into the nuclei of such cells, proving that LEF-1 does transport endogenous β-catenin into nuclei. Moreover, transfection of uveal melanoma cells with B-box deficient LEF-1 inhibits nuclear import of β-catenin by endogenous LEF-1. However, the movement of overexpressed exogenous β-catenin into nuclei is unaffected by the presence or absence of LEF-l and forms abnormal nuclear aggregates that are a prelude to subsequent apoptosis. We conclude that nuclear transport of exogenous β-catenin independently of LEF-1 has questionable physiological significance.
Dendrite-like Process Formation and Cytoskeletal Remodeling Regulated by δ-Catenin expression
Kim, Kwonseop,Sirota, Anna,Chen, Yan-hua,Jones, Shiloh B.,Dudek, Ronald,Lanford, George W.,Thakore, Chittam,Lu, Qun 전남대학교 약품개발연구소 2002 약품개발연구지 Vol.11 No.-
Actin- and microtubule-mediated changes in cell shape are essential for many cellular activities. However, the molecular mechanisms underlying the interplay between the two are complex and remain obscure. Here we show that the expression of δ-catenin (or NPRAP/Neurojungin), a member of p120^ctm subfamily of armadillo proteins can induce the branching of dendrite-like processes in 3T3 cells and enhance dendritic morphogenesis in primary hippocampal neurons. This induction of branching phenotype involves initially the disruption of filamentous actin, and requires the growth of microtubules. The carboxyl-terminal truncation mutant of δ-catenin can cluster and redistribute the full-length protein, and dominantly inhibit its branching effect. δ-Catenin forms protein complexes and can bind directly to actin in vitro. The carboxyl-terminal truncation of δ-catenin does not interfere with its actin-binding capability; therefore the actin interaction alone is not sufficient for the induction of dendrite-like processes. When δ-catenin-transformed cells establish elaborate dendrite-like branches, the main cellular processes become stabilized and resist the disruption od both actin filaments and microscopy and time-lapse recording analyses. We suggest that δ-catenin can effect a biphasic cytoskeletal remodeling event which differentially regulates actin and microtubules and promotes cellular morphogenesis.
( Yongfeng He ),( Hangun Kim ),( Taeyong Ryu ),( Youra Kang ),( Jeong Ae Kim ),( Bo Hyun Kim ),( Jae Hyuk Lee ),( Keonwook Kang ),( Qun Lu ),( Kwonseop Kim ) 영남대학교 약품개발연구소 2013 영남대학교 약품개발연구소 연구업적집 Vol.23 No.0
This study revealed that CWR22Rv-1 cells overexpressing δ-catenin display bigger tumor formation and higher angiogenic potentials than their matched control cells in the CAM assay. In addition, δ-catenin overexpression in CWR22Rv-1 cells results in increased hypoxia-inducible factor 1-alpha (HIF-1α and vascular endothelial growth factor (VEGF) expression. Furthermore, δ-catenin overexpression was found to enhance nuclear distribution of both β-catenin and HIF-1α in hypoxic condition, which is diminished by knockdown of δ-catenin. Our current study adds novel evidence regarding contribution of δ-catenin to the progression of prostate cancer. ⓒ2012 Federation of European Biochemical Societies. Published by Elsevier B.v.All rights reserved.
Improved memory and reduced anxiety in δ-catenin transgenic mice
Ryu, Taeyong,Park, Hyung Joon,Kim, Hangun,Cho, Young-Chang,Kim, Byeong C.,Jo, Jihoon,Seo, Young-Woo,Choi, Won-Seok,Kim, Kwonseop Academic Press 2019 Experimental neurology Vol.318 No.-
<P><B>Abstract</B></P> <P>δ-Catenin is abundant in the brain and affects its synaptic plasticity. Furthermore, loss of δ-catenin is related to the deficits of learning and memory, mental retardation (cri-du-chat syndrome), and autism. A few studies about δ-catenin deficiency mice were performed. However, the effect of δ-catenin overexpression in the brain has not been investigated as yet. Therefore we generated a δ-catenin overexpressing mouse model. To generate a transgenic mouse model overexpressing δ-catenin in the brain, δ-catenin plasmid having a Thy-1 promotor was microinjected in C57BL/6 mice. Our results showed δ-catenin transgenic mice expressed higher levels of N-cadherin, β-catenin, and p120-catenin than did wild type mice. Furthermore, δ-catenin transgenic mice exhibited better object recognition, better sociability, and lower anxiety than wild type mice. However, both mice groups showed a similar pattern in locomotion tests. Although δ-catenin transgenic mice show similar locomotion, they show improved sociability and reduced anxiety. These characteristics are opposite to the symptoms of autism or mental retardation, which are caused when δ-catenin is deficient. These results suggest that δ-catenin may alleviate symptoms of autism, Alzheimer's disease and mental retardation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> δ-Catenin transgenic mice had improved object recognition. </LI> <LI> δ-Catenin transgenic mice showed improved social interactions. </LI> <LI> δ-Catenin transgenic mice showed less anxiety. </LI> </UL> </P>
( Yong Feng He ),( Hang Gun Kim ),( Tae Yong Ryu ),( Kwang Youl Lee ),( Won Seok Choi ),( Kyeong Man Kim ),( Mei Zheng ),( Yechan Joh ),( Jae Hyuk Lee ),( Dong Deuk Kwon ),( Qun Lu ),( Kwonseop Kim ) 전남대학교 약품개발연구소 2014 약품개발연구지 Vol.23 No.-
&-catenin was first considered as a brain spedfic protein, strong evidence of&-catenin overexpression in various cancers, including prostate cancer, has been accumulated. Phosphorylation of a-catenin by Akt and GSK313 has been studied in various cell lines. However, tyrosine phosphorylation of &-catenin in prostate cancer cells remains unknown. In the current study, we demonstrated that Src kinase itself phosphorylates &-catenin on its tyrosine residues in prostate cancer cells and further illustrated that Yl073, Yll12 and Yl176 of &-catenin are predominant sites responsible for tyrosine phosphorylation mediated by c-Src. Apart from c-Src, other Src family kinases, including Fgr, Fyn and Lyn, can also phosphorylate a-catenin. We also found that c-Src-mediated Tyr-phosphorylation of &-catenin increases its stability via decreasing its affinity to GSK313 and enhances its ability of indudng nuclear distribution of j3-catenin through interrupting the integrity of the E-cadherin. Taken together, these results indicate that c-Src can enhance the oncogenic function of&-catenin in prostate cancer cells. ⓒ 2013 Elsevier B.V. All rights reserved.