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Gu, Changkyu,Shim, Sungbo,Shin, Jongdae,Kim, Jieun,Park, Jonghoon,Han, Kyuhyung,Park, Soochul Nature Publishing Group 2005 Oncogene Vol.24 No.26
Recent studies in our laboratory demonstrate that ligand-mediated activation of the EphA8 receptor critically regulates cell adhesion and migration. In this report, we show that the EphA8 receptor induces neurite outgrowth in NG108-15 cells in the absence of ligand stimulation. Using various deletion mutants lacking specific intracytoplasmic regions, we confirm that the tyrosine kinase domain of EphA8 is important for inducing neurite outgrowth. However, the tyrosine kinase activity of EphA8 is not crucial for neurite outgrowth induction. Treatment with various inhibitors further reveals that the mitogen-activated protein kinase (MAPK) signaling pathway is critical for neurite outgrowth induced by EphA8. Consistent with these results, EphA8 expression induced a sustained increase in the activity of MAPK, whereas ligand-mediated EphA8 activation had no further modulatory effects on MAP kinase activity. Additionally, activated MAPK relocalized from the cytoplasm to the nucleus in response to EphA8 transfection. These results collectively suggest that the EphA8 receptor is capable of inducing a sustained increase in MAPK activity, thereby promoting neurite outgrowth in neuronal cells.Oncogene (2005) 24, 4243–4256. doi:10.1038/sj.onc.1208584 Published online 14 March 2005
Shin, Jongdae,Gu, Changkyu,Park, Eunjeong,Park, Soochul American Society for Microbiology 2007 Molecular and cellular biology Vol.27 No.23
<B>ABSTRACT</B><P>Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-1b and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA-1b and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required for this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells. Taken together, our findings support a possible function for Anks family proteins as scaffolding proteins of the EphA8 signaling pathway.</P>
Shin, Jongdae,Gu, Changkyu,Park, Eunjeong,Park, Soochul Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.1
Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-lb and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA- lb and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required far this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a tells. Taken together, our findings support a possible function far Anks family proteins as scaffolding proteins of the EphA8 signaling pathway.
Choi, Jin-Ho,Shin, Young-Lim,Kim, Gu-Hwan,Kim, Youngho,Park, Sangwook,Park, Jung-Young,Oh, Changkyu,Yoo, Han-Wook S. Karger AG 2005 Hormone research Vol.63 No.4
<P><I>Objective:</I> X-linked adrenal hypoplasia congenita (AHC) is a condition clinically featuring adrenal insufficiency and hypogonadotropic hypogonadism caused by mutations of <I>DAX-1</I>. This study was undertaken to characterize the molecular defects of <I>DAX-1</I> in 3 unrelated Korean patients with AHC. <I>Patients and Methods:</I> Patient 1 is a 6-year-old boy who presented with a salt-losing adrenal crisis in the neonatal period. Patient 2 is a 3-year-old boy who manifested aspiration pneumonia and adrenal insufficiency at the age of 1 month. Patient 3 is a 7-year-old boy who developed an adrenal crisis at the age of 3 days. In each of these patients, <I>DAX-1</I> was analyzed by direct DNA sequencing after polymerase chain reaction amplification of the entire coding region. <I>Results:</I> Direct sequencing of <I>DAX-1</I> revealed two novel mutations, 1156_1157delCT in patient 1 and another novel nonsense mutation W105X in patient 2. Patient 3 had complete deletion of <I>DAX-1</I>. In patient 3, serum transaminases and creatine kinase levels were elevated while the glycerol kinase activity of leukocytes was decreased. Markedly elevated glycerol excretion was detected by urine organic acid analysis. Patient 3 was diagnosed as Xp21 contiguous gene syndrome associated with deletions of the entire <I>IL1RAPL</I>, <I>GK</I> genes and the C-terminal region of <I>DMD </I>gene. <I>Conclusions:</I> Two novel mutations of <I>DAX-1</I> were detected in 2 unrelated patients with AHC, and complete deletion of <I>DAX-1</I> in a patient with Xp21 contiguous gene syndrome who also presented with glycerol kinase deficiency, Duchenne muscular dystrophy, and AHC.</P><P>Copyright © 2005 S. Karger AG, Basel</P>