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Kim, Eui,Kim, Do-Hyeon,Singaram, Indira,Jeong, Heeyoon,Koh, Ara,Lee, Jiyoun,Cho, Wonhwa,Ryu, Sung Ho Elsevier 2018 Cellular signalling Vol.51 No.-
<P><B>Abstract</B></P> <P>Regulation of tyrosine phosphorylation on insulin receptor substrate-1 (IRS-1) is essential for insulin signaling. The protein tyrosine phosphatase (PTP) C1-Ten/Tensin2 has been implicated in the regulation of IRS-1, but the molecular basis of this dephosphorylation is not fully understood. Here, we demonstrate that the cellular phosphatase activity of C1-Ten/Tensin2 on IRS-1 is mediated by the binding of the C1-Ten/Tensin2 Src-homology 2 (SH2) domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P<SUB>3</SUB>). We show that the role of C1-Ten/Tensin2 is dependent on insulin-induced phosphoinositide 3-kinase activity. The C1-Ten/Tensin2 SH2 domain showed strong preference and high affinity for PtdIns(3,4,5)P<SUB>3</SUB>. Using site-directed mutagenesis, we identified three basic residues in the C1-Ten/Tensin2 SH2 domain that were critical for PtdIns(3,4,5)P<SUB>3</SUB> binding but were not involved in phosphotyrosine binding and PTP activity. Using a PtdIns(3,4,5)P<SUB>3</SUB> binding-deficient mutant, we showed that the specific binding of the C1-Ten/Tensin2 SH2 domain to PtdIns(3,4,5)P<SUB>3</SUB> allowed C1-Ten/Tensin2 to function as a PTP in cells. Collectively, our findings suggest that the interaction between the C1-Ten/Tensin2 SH2 domain and PtdIns(3,4,5)P<SUB>3</SUB> produces a negative feedback loop of insulin signaling through IRS-1.</P> <P><B>Highlights</B></P> <P> <UL> <LI> C1-Ten's function as a PTP for IRS-1 in insulin signaling is controlled by PI3K. </LI> <LI> The C1-Ten SH2 domain binds to PtdIns(3,4,5)P<SUB>3</SUB> with high affinity. </LI> <LI> The PtdIns(3,4,5)P<SUB>3</SUB> binding of C1-Ten is necessary for its function as PTP. </LI> </UL> </P>
Ahn, Bum Ju,Le, Hoang,Shin, Min Wook,Bae, Sung-Jin,Lee, Eun Ji,Lee, Sung Yi,Yang, Ju Hee,Wee, Hee-Jun,Cha, Jong-Ho,Seo, Ji Hae,Lee, Hye Shin,Lee, Hyo-Jong,Arai, Ken,Lo, Eng H.,Jeon, Sejin,Oh, Goo Taeg American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.32
<P>Ninjurin1 is involved in the pathogenesis of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, by mediating leukocyte extravasation, a process that depends on homotypic binding. However, the precise regulatory mechanisms of Ninjurin1 during inflammation are largely undefined. We therefore examined the pro-migratory function of Ninjurin1 and its regulatory mechanisms in macrophages. Interestingly, Ninjurin1-deficient bone marrow-derived macrophages exhibited reduced membrane protrusion formation and dynamics, resulting in the impairment of cell motility. Furthermore, exogenous Ninjurin1 was distributed at the membrane of filopodial structures in Raw264.7 macrophage cells. In Raw264.7 cells, RNA interference of Ninjurin1 reduced the number of filopodial projections, whereas overexpression of Ninjurin1 facilitated their formation and thus promoted cell motility. Ninjurin1-induced filopodial protrusion formation required the activation of Rac1. In Raw264.7 cells penetrating an MBEC4 endothelial cell monolayer, Ninjurin1 was localized to the membrane of protrusions and promoted their formation, suggesting that Ninjurin1-induced protrusive activity contributed to transendothelial migration. Taking these data together, we conclude that Ninjurin1 enhances macrophage motility and consequent extravasation of immune cells through the regulation of protrusive membrane dynamics. We expect these findings to provide insight into the understanding of immune responses mediated by Ninjurin1.</P>
Kim, Yoonju,Lee, Sang-Eun,Park, Joohyun,Kim, Minhyung,Lee, Boyoon,Hwang, Daehee,Chang, Sunghoe American Society for Biochemistry and Molecular Bi 2015 The Journal of biological chemistry Vol.290 No.12
<P>Recent studies have reported conflicting results regarding the role of ARF6 in dendritic spine development, but no clear answer for the controversy has been suggested. We found that ADP-ribosylation factor 6 (ARF6) either positively or negatively regulates dendritic spine formation depending on neuronal maturation and activity. ARF6 activation increased the spine formation in developing neurons, whereas it decreased spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite patterns of expression of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via the phospholipase D pathway is the coincident factor in both stages, but the antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using tetrodotoxin or enhancing the activity in mature neurons using picrotoxin or chemical long term potentiation reversed the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated spine structures may play a role in structural plasticity of mature neurons.</P>