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E. Premkumar Reddy - One of the best experts on this subject based on the ideXlab platform.
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JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1
The Journal of biological chemistry, 2015Co-Authors: Poornima Ramkumar, Clement M. Lee, Annie Moradian, Michael J. Sweredoski, Sonja Hess, Andrew D. Sharrocks, Dale S. Haines, E. Premkumar ReddyAbstract:JLP (JNK-associated Leucine Zipper Protein) is a scaffolding Protein that interacts with various signaling Proteins associated with coordinated regulation of cellular process such as endocytosis, motility, neurite outgrowth, cell proliferation, and apoptosis. Here we identified PLK1 (Polo-like kinase 1) as a novel interaction partner of JLP through mass spectrometric approaches. Our results indicate that JLP is phospho-primed by PLK1 on Thr-351, which is recognized by the Polo box domain of PLK1 leading to phosphorylation of JLP at additional sites. Stable isotope labeling by amino acids in cell culture and quantitative LC-MS/MS analysis was performed to identify PLK1-dependent JLP-interacting Proteins. Treatment of cells with the PLK1 kinase inhibitor BI2536 suppressed binding of the Forkhead box Protein K1 (FOXK1) transcriptional repressor to JLP. JLP was found to interact with PLK1 and FOXK1 during mitosis. Moreover, knockdown of PLK1 affected the interaction between JLP and FOXK1. FOXK1 is a known transcriptional repressor of the CDK inhibitor p21/WAF1, and knockdown of JLP resulted in increased FOXK1 Protein levels and a reduction of p21 transcript levels. Our results suggest a novel mechanism by which FOXK1 Protein levels and activity are regulated by associating with JLP and PLK1.
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Neoplastic transformation induced by the gep oncogenes involves the scaffold Protein JNK-interacting Leucine Zipper Protein.
Neoplasia (New York N.Y.), 2011Co-Authors: Kimia Kashef, Clement M. Lee, E. Premkumar Reddy, Rangasudhagar Radhakrishnan, Danny N. DhanasekaranAbstract:The activated mutants of the α-subunits of G Proteins G12 and G13 have been designated as the gep oncogenes owing to their ability to stimulate diverse oncogenic signaling pathways that lead to neoplastic transformation of fibroblast cell lines and tumorigenesis in nude mice models. Studies from our laboratory as well as others have shown that the growth-promoting activities of Gα12 and Gα13 involve potent activation of c-Jun N-terminal kinases (JNKs). Our previous studies have indicated that the JNK-interacting Leucine Zipper Protein (JLP), a scaffold Protein involved in the structural and functional organization of the JNK/p38 mitogen-activated Protein kinase module, tethers Gα12 and Gα13 to the JNK signaling module. In the present study, in addition to demonstrating the physical association between JLP and Gα12, we show that this interaction is enhanced by the receptor- or mutation-mediated activation of Gα12. We also establish that JLP interacts with Gα12 through the C-terminal domain that has been previously identified to be involved in binding to Gα13. Furthermore, using this C-terminal domain as a competitively inhibitor of JLP that can disrupt Gα12-JLP interaction, we demonstrate that JLP is required for the stimulation of JNK by Gα12. Our results also indicate that such JLP interaction is required for Gα12 as well as Gα13-mediated neoplastic transformation of JLP. These studies demonstrate for the first time a functional role for JLP in the gep oncogene-regulated neoplastic signaling pathway.
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Regulation of neurite outgrowth by interactions between the scaffolding Protein, JNK-associated Leucine Zipper Protein, and neuronal growth-associated Protein superior cervical ganglia clone 10.
The Journal of biological chemistry, 2009Co-Authors: Danny N. Dhanasekaran, Clement M. Lee, E. Premkumar ReddyAbstract:Abstract JLP (JNK-associated Leucine Zipper Protein) is a novel scaffolding Protein involved in JNK signaling. Although it is known that JLP is highly expressed in brain, the biological function of JLP in neuronal systems remains unknown. Here, we report a novel interaction between JLP and SCG10 (superior cervical ganglia clone 10), which is a microtubule-destabilizing factor that is essential for neurite outgrowth. Inhibition of endogenous JLP expression using small interference RNA methodology strongly enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Our results show that JLP negatively regulates NGF-induced neurite outgrowth by decreasing the level of phosphorylated SCG10. Furthermore, inhibition of JNK phosphorylation by a small molecule inhibitor, SP600125, resulted in inhibition of SCG10 phosphorylation and inhibition of neurite growth. Taken together, our results suggest that JLP negatively regulates NGF-induced neurite outgrowth through a sequestering mechanism that results in an attenuation of NGF-induced SCG10 phosphorylation.
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JNK-Interacting Leucine Zipper Protein Is a Novel Scaffolding Protein in the Gα13 Signaling Pathway†
Biochemistry, 2005Co-Authors: Kimia Kashef, Clement M. Lee, E. Premkumar Reddy, Danny N. DhanasekaranAbstract:Abstract Scaffolding Proteins play a critical role in conferring specificity and fidelity to signaling pathways. The JNK-interacting Leucine Zipper Protein (JLP) has been identified as a scaffolding Protein involved in linking components of the JNK signaling module. Galpha(12) and Galpha(13), the alpha-subunits of heterotrimeric G Proteins G12 and G13, respectively, stimulate the JNK module in diverse cell types. Here, we report that Galpha(13) physically interacts with JLP, and this interaction enhances Galpha(13)-mediated JNK activation. We also demonstrate endogenous interaction between JLP and Galpha(13) in MCF-7 cells. JLP interaction is specific to the G12 family of alpha-subunits via its C-terminal domain (termed GID-JLP), spanning amino acids 1165-1307, and this interaction is more pronounced with the mutationally or functionally activated form of Galpha(13) compared to that of wild-type Galpha(13). The presence of a ternary complex consisting of Galpha(13), JLP, and JNK suggests a role for JLP in tethering Galpha(13) to the signaling components involved in JNK activation. Coexpression of GID-JLP disrupts ternary complex formation in addition to attenuating Galpha(13)-stimulated JNK activity. These findings identify JLP as a novel scaffolding Protein in the Galpha(13)-mediated JNK signaling pathway.
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JLP: a scaffolding Protein that tethers JNK/p38MAPK signaling modules and transcription factors
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Clement M. Lee, Djamila Onesime, C Damodara Reddy, N Dhanasekaran, E. Premkumar ReddyAbstract:Extracellular signals are transduced into cells through mitogen-activated Protein kinases (MAPKs), which are activated by their upstream kinases. Recently, families of scaffolding Proteins have been identified to tether specific combinations of these kinases along specific signaling pathways. Here we describe a Protein, JLP (c-Jun NH2-terminal kinase-associated Leucine Zipper Protein), which acts as a scaffolding Protein to bring together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3). Thus, JLP defines a family of scaffolding Proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways.
Stuart H Orkin - One of the best experts on this subject based on the ideXlab platform.
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erythroid transcription factor nf e2 is a haematopoietic specific basic Leucine Zipper Protein
Nature, 1993Co-Authors: Nancy C Andrews, Hediye Erdjumentbromage, Mark B Davidson, Paul Tempst, Stuart H OrkinAbstract:Expression of globin genes in developing erythroid cells is controlled by upstream locus control regions. Activity of these regions in vivo requires an erythroid-specific nuclear factor (NF-E2) that binds AP-1-like recognition sites. Its tissue-specific component (p45 NF-E2) has been characterized by complementary DNA cloning as a new basic region–Leucine Zipper Protein which dimerizes with a ubiquitous partner to form native NF-E2.
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Erythroid transcription factor NF-E2 is a haematopoietic-specific basic–Leucine Zipper Protein
Nature, 1993Co-Authors: Nancy C Andrews, Mark B Davidson, Paul Tempst, Hediye Erdjument-bromage, Stuart H OrkinAbstract:Expression of globin genes in developing erythroid cells is controlled by upstream locus control regions. Activity of these regions in vivo requires an erythroid-specific nuclear factor (NF-E2) that binds AP-1-like recognition sites. Its tissue-specific component (p45 NF-E2) has been characterized by complementary DNA cloning as a new basic region–Leucine Zipper Protein which dimerizes with a ubiquitous partner to form native NF-E2.
Syu-ichi Hirai - One of the best experts on this subject based on the ideXlab platform.
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mapk upstream kinase muk binding inhibitory Protein a negative regulator of muk dual Leucine Zipper bearing kinase Leucine Zipper Protein kinase
Journal of Biological Chemistry, 2000Co-Authors: Keiko Fukuyama, Akio Yamashita, Tetsuya Deyama, Masaya Baba, Atsushi Suzuki, Hiroshi Mohri, Zenro Ikezawa, Hiroshi Nakajima, M Yoshida, Syu-ichi HiraiAbstract:Mitogen-activated Protein kinase upstream kinase/dual Leucine Zipper-bearing kinase/Leucine-Zipper Protein kinase (MUK/DLK/ZPK) is a MAPKKK class Protein kinase that induces JNK/SAPK activation. We report here a Protein named MBIP that binds to MUK/DLK/ZPK. MUK-binding inhibitory Protein (MBIP) contains two tandemly orientated Leucine-Zipper-like motifs with a cluster of basic amino acids located between the two motifs. MBIP interacts with one of the two Leucine-Zipper-like motifs of MUK/DLK/ZPK and inhibits the activity of MUK/DLK/ZPK to induce JNK/SAPK activation. Notably, no similar effect was observed with another JNK/SAPK-inducing MAPKKK, COT/Tpl-2, showing the specificity of MBIP action. Furthermore, the overexpression of MBIP partially inhibits the activation of JNK by 0.3 m sorbitol in 293T cells. Taken together, these observations indicate that MBIP can function as a regulator of MUK/DLK/ZPK, a finding that may provide a clue to understanding the molecular mechanism of JNK/SAPK activation by hyperosmotic stress.
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MAPK upstream kinase (MUK)-binding inhibitory Protein, a negative regulator of MUK/dual Leucine Zipper-bearing kinase/Leucine Zipper Protein kinase.
The Journal of biological chemistry, 2000Co-Authors: Keiko Fukuyama, Yoshida M, Akio Yamashita, Tetsuya Deyama, Masaya Baba, Atsushi Suzuki, Hiroshi Mohri, Zenro Ikezawa, Hiroshi Nakajima, Syu-ichi HiraiAbstract:Mitogen-activated Protein kinase upstream kinase/dual Leucine Zipper-bearing kinase/Leucine-Zipper Protein kinase (MUK/DLK/ZPK) is a MAPKKK class Protein kinase that induces JNK/SAPK activation. We report here a Protein named MBIP that binds to MUK/DLK/ZPK. MUK-binding inhibitory Protein (MBIP) contains two tandemly orientated Leucine-Zipper-like motifs with a cluster of basic amino acids located between the two motifs. MBIP interacts with one of the two Leucine-Zipper-like motifs of MUK/DLK/ZPK and inhibits the activity of MUK/DLK/ZPK to induce JNK/SAPK activation. Notably, no similar effect was observed with another JNK/SAPK-inducing MAPKKK, COT/Tpl-2, showing the specificity of MBIP action. Furthermore, the overexpression of MBIP partially inhibits the activation of JNK by 0.3 m sorbitol in 293T cells. Taken together, these observations indicate that MBIP can function as a regulator of MUK/DLK/ZPK, a finding that may provide a clue to understanding the molecular mechanism of JNK/SAPK activation by hyperosmotic stress.
Clement M. Lee - One of the best experts on this subject based on the ideXlab platform.
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JNK-associated Leucine Zipper Protein Functions as a Docking Platform for Polo-like Kinase 1 and Regulation of the Associating Transcription Factor Forkhead Box Protein K1
The Journal of biological chemistry, 2015Co-Authors: Poornima Ramkumar, Clement M. Lee, Annie Moradian, Michael J. Sweredoski, Sonja Hess, Andrew D. Sharrocks, Dale S. Haines, E. Premkumar ReddyAbstract:JLP (JNK-associated Leucine Zipper Protein) is a scaffolding Protein that interacts with various signaling Proteins associated with coordinated regulation of cellular process such as endocytosis, motility, neurite outgrowth, cell proliferation, and apoptosis. Here we identified PLK1 (Polo-like kinase 1) as a novel interaction partner of JLP through mass spectrometric approaches. Our results indicate that JLP is phospho-primed by PLK1 on Thr-351, which is recognized by the Polo box domain of PLK1 leading to phosphorylation of JLP at additional sites. Stable isotope labeling by amino acids in cell culture and quantitative LC-MS/MS analysis was performed to identify PLK1-dependent JLP-interacting Proteins. Treatment of cells with the PLK1 kinase inhibitor BI2536 suppressed binding of the Forkhead box Protein K1 (FOXK1) transcriptional repressor to JLP. JLP was found to interact with PLK1 and FOXK1 during mitosis. Moreover, knockdown of PLK1 affected the interaction between JLP and FOXK1. FOXK1 is a known transcriptional repressor of the CDK inhibitor p21/WAF1, and knockdown of JLP resulted in increased FOXK1 Protein levels and a reduction of p21 transcript levels. Our results suggest a novel mechanism by which FOXK1 Protein levels and activity are regulated by associating with JLP and PLK1.
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Neoplastic transformation induced by the gep oncogenes involves the scaffold Protein JNK-interacting Leucine Zipper Protein.
Neoplasia (New York N.Y.), 2011Co-Authors: Kimia Kashef, Clement M. Lee, E. Premkumar Reddy, Rangasudhagar Radhakrishnan, Danny N. DhanasekaranAbstract:The activated mutants of the α-subunits of G Proteins G12 and G13 have been designated as the gep oncogenes owing to their ability to stimulate diverse oncogenic signaling pathways that lead to neoplastic transformation of fibroblast cell lines and tumorigenesis in nude mice models. Studies from our laboratory as well as others have shown that the growth-promoting activities of Gα12 and Gα13 involve potent activation of c-Jun N-terminal kinases (JNKs). Our previous studies have indicated that the JNK-interacting Leucine Zipper Protein (JLP), a scaffold Protein involved in the structural and functional organization of the JNK/p38 mitogen-activated Protein kinase module, tethers Gα12 and Gα13 to the JNK signaling module. In the present study, in addition to demonstrating the physical association between JLP and Gα12, we show that this interaction is enhanced by the receptor- or mutation-mediated activation of Gα12. We also establish that JLP interacts with Gα12 through the C-terminal domain that has been previously identified to be involved in binding to Gα13. Furthermore, using this C-terminal domain as a competitively inhibitor of JLP that can disrupt Gα12-JLP interaction, we demonstrate that JLP is required for the stimulation of JNK by Gα12. Our results also indicate that such JLP interaction is required for Gα12 as well as Gα13-mediated neoplastic transformation of JLP. These studies demonstrate for the first time a functional role for JLP in the gep oncogene-regulated neoplastic signaling pathway.
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Regulation of neurite outgrowth by interactions between the scaffolding Protein, JNK-associated Leucine Zipper Protein, and neuronal growth-associated Protein superior cervical ganglia clone 10.
The Journal of biological chemistry, 2009Co-Authors: Danny N. Dhanasekaran, Clement M. Lee, E. Premkumar ReddyAbstract:Abstract JLP (JNK-associated Leucine Zipper Protein) is a novel scaffolding Protein involved in JNK signaling. Although it is known that JLP is highly expressed in brain, the biological function of JLP in neuronal systems remains unknown. Here, we report a novel interaction between JLP and SCG10 (superior cervical ganglia clone 10), which is a microtubule-destabilizing factor that is essential for neurite outgrowth. Inhibition of endogenous JLP expression using small interference RNA methodology strongly enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Our results show that JLP negatively regulates NGF-induced neurite outgrowth by decreasing the level of phosphorylated SCG10. Furthermore, inhibition of JNK phosphorylation by a small molecule inhibitor, SP600125, resulted in inhibition of SCG10 phosphorylation and inhibition of neurite growth. Taken together, our results suggest that JLP negatively regulates NGF-induced neurite outgrowth through a sequestering mechanism that results in an attenuation of NGF-induced SCG10 phosphorylation.
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JNK-Interacting Leucine Zipper Protein Is a Novel Scaffolding Protein in the Gα13 Signaling Pathway†
Biochemistry, 2005Co-Authors: Kimia Kashef, Clement M. Lee, E. Premkumar Reddy, Danny N. DhanasekaranAbstract:Abstract Scaffolding Proteins play a critical role in conferring specificity and fidelity to signaling pathways. The JNK-interacting Leucine Zipper Protein (JLP) has been identified as a scaffolding Protein involved in linking components of the JNK signaling module. Galpha(12) and Galpha(13), the alpha-subunits of heterotrimeric G Proteins G12 and G13, respectively, stimulate the JNK module in diverse cell types. Here, we report that Galpha(13) physically interacts with JLP, and this interaction enhances Galpha(13)-mediated JNK activation. We also demonstrate endogenous interaction between JLP and Galpha(13) in MCF-7 cells. JLP interaction is specific to the G12 family of alpha-subunits via its C-terminal domain (termed GID-JLP), spanning amino acids 1165-1307, and this interaction is more pronounced with the mutationally or functionally activated form of Galpha(13) compared to that of wild-type Galpha(13). The presence of a ternary complex consisting of Galpha(13), JLP, and JNK suggests a role for JLP in tethering Galpha(13) to the signaling components involved in JNK activation. Coexpression of GID-JLP disrupts ternary complex formation in addition to attenuating Galpha(13)-stimulated JNK activity. These findings identify JLP as a novel scaffolding Protein in the Galpha(13)-mediated JNK signaling pathway.
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JLP: a scaffolding Protein that tethers JNK/p38MAPK signaling modules and transcription factors
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Clement M. Lee, Djamila Onesime, C Damodara Reddy, N Dhanasekaran, E. Premkumar ReddyAbstract:Extracellular signals are transduced into cells through mitogen-activated Protein kinases (MAPKs), which are activated by their upstream kinases. Recently, families of scaffolding Proteins have been identified to tether specific combinations of these kinases along specific signaling pathways. Here we describe a Protein, JLP (c-Jun NH2-terminal kinase-associated Leucine Zipper Protein), which acts as a scaffolding Protein to bring together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3). Thus, JLP defines a family of scaffolding Proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways.
Katsuji Yoshioka - One of the best experts on this subject based on the ideXlab platform.
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A negative feedback loop between JNK-associated Leucine Zipper Protein and TGF-β1 regulates kidney fibrosis.
Communications biology, 2020Co-Authors: Qi Yan, Katsuji Yoshioka, Kai Zhu, Lu Zhang, Zhaowei Chen, Shan Liu, Ryota Nakazato, Bo DiaoAbstract:Renal fibrosis is controlled by profibrotic and antifibrotic forces. Exploring anti-fibrosis factors and mechanisms is an attractive strategy to prevent organ failure. Here we identified the JNK-associated Leucine Zipper Protein (JLP) as a potential endogenous antifibrotic factor. JLP, predominantly expressed in renal tubular epithelial cells (TECs) in normal human or mouse kidneys, was downregulated in fibrotic kidneys. Jlp deficiency resulted in more severe renal fibrosis in unilateral ureteral obstruction (UUO) mice, while renal fibrosis resistance was observed in TECs-specific transgenic Jlp mice. JLP executes its protective role in renal fibrosis via negatively regulating TGF-β1 expression and autophagy, and the profibrotic effects of ECM production, epithelial-to-mesenchymal transition (EMT), apoptosis and cell cycle arrest in TECs. We further found that TGF-β1 and FGF-2 could negatively regulate the expression of JLP. Our study suggests that JLP plays a central role in renal fibrosis via its negative crosstalk with the profibrotic factor, TGF-β1.
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Functional role of c-Jun NH2-terminal kinase-associated Leucine Zipper Protein (JLP) in lysosome localization and autophagy.
Drug discoveries & therapeutics, 2020Co-Authors: Ryusuke Suzuki, I Ketut Gunarta, Jambaldorj Boldbaatar, Purev Erdenebaatar, Ravdandorj Odongoo, Katsuji YoshiokaAbstract:Lysosomes are involved in many cellular functions, and in turn lysosomal dysfunction underlies a variety of diseases, including cancer and neurodegenerative diseases. Lysosomes are distributed broadly in the cytoplasm and can move throughout the cell in kinesin- and dynein-dependent manners. Although many mechanisms of lysosomal transport have been reported, how lysosomal transport is regulated has yet to be fully elucidated. In this study we analyzed c-Jun NH2-terminal kinase-associated Leucine Zipper Protein (JLP), an adaptor of kinesin and dynein motor Proteins, and found that lysosomes were localized toward the cell periphery in JLP knockdown cells, leading to the impairment of autophagosome-lysosome fusion. Furthermore, we performed rescue experiments using wild-type JLP and its various deletion mutants. The results indicated that JLP may regulate lysosome localization and autophagy through interaction of JLP with kinesin-1 heavy chain, but not with dynactin p150Glued or lysosomal transmembrane Protein 55b. Our findings provide new insights into the mechanisms of lysosomal trafficking regulation. This study contributes to the understanding of how lysosomes exert their multiple functions, potentially leading to the identification of molecular targets for diseases caused by lysosomal dysfunction.
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Protective role of c-Jun NH2-terminal kinase-associated Leucine Zipper Protein (JLP) in curcumin-induced cancer cell death.
Biochemical and biophysical research communications, 2019Co-Authors: Jambaldorj Boldbaatar, Ryusuke Suzuki, I Ketut Gunarta, Purev Erdenebaatar, Gantulga Davaakhuu, Hirohiko Hohjoh, Katsuji YoshiokaAbstract:Previous studies have established the antitumor activity of curcumin, a major component of turmeric. Increasing evidence indicates that curcumin induces autophagy, the activation of mitogen-activated Protein kinase (MAPK) intracellular signaling pathways, and reactive oxygen species (ROS)-mediated cell death. The c-Jun NH2-terminal kinase (JNK)-associated Leucine Zipper Protein (JLP), a scaffold Protein for MAPK signaling pathways, has been identified as a candidate biomarker for cancer. In this study, we explored the role of JLP in curcumin-induced cancer cell death. We found that JLP knockdown (KD) increases cell death and intracellular ROS levels. Furthermore, JLP KD impaired lysosomal accumulation around perinuclear regions, which led to the inhibition of autophagosome-lysosome fusion, and attenuated p38 MAPK activation in curcumin-treated cells. The decreases in cell viability and p38 MAPK activation were reversed by expressing wild-type JLP but not a JLP mutant lacking the p38 MAPK-binding domain. In addition, the inactivation of a key gene involved in autophagy increased sensitivity to curcumin-induced cell death. Together, these results suggest that JLP mediates the induction of autophagy by regulating lysosome positioning and p38 MAPK signaling, indicating an overall protective role in curcumin-induced ROS-mediated cancer cell death.
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N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein: IMPLICATIONS FOR NEURODEGENERATION IN ALZHEIMER DISEASE
The Journal of biological chemistry, 2010Co-Authors: Koichi Ando, Katsuji Yoshioka, Kengo Uemura, Akira Kuzuya, Masato Maesako, Megumi Asada-utsugi, Masakazu Kubota, Nobuhisa Aoyagi, Katsuya Okawa, Haruhisa InoueAbstract:Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with Aβ(42) decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated Leucine Zipper Protein (JLP), a scaffolding Protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherin-based synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by Aβ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.
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The Scaffold Protein c-Jun NH2-Terminal Kinase-associated Leucine Zipper Protein Regulates Cell Migration through Interaction with the G Protein Gα13
Journal of Biochemistry, 2008Co-Authors: Davaakhuu Gantulga, Baljinnyam Tuvshintugs, Yoshio Endo, Takahisa Takino, Seishi Murakami, Hiroshi Sato, Katsuji YoshiokaAbstract:Scaffold Proteins for MAP kinase (MAPK) signalling modules play an important role in the specific and efficient signal transduction of the relevant MAPK cascades. Here, we investigated the function of the scaffolding Protein c-Jun NH 2 -terminal kinase (JNK)-associated Leucine Zipper Protein (JLP) by depleting it in cultured cells using a short hairpin RNA (shRNA) against human JLP. HeLa and DLD-1 cells stably expressing the shRNA showed a defect in cell migration. The re-expression of full-length shRNA-resistant mouse JLP rescued the impaired cell migration of the JLP-depleted HeLa cells; whereas, a C-terminal deletion mutant of mouse JLP, which failed to bind the G Protein G α13 , showed little or no effect on the cell migration defect. Furthermore, although a constitutively active G α13 enhanced the migration of control HeLa cells, the G α13 -induced cell migration was significantly suppressed in the JLP-depleted HeLa cells. Taken together, these results suggest that JLP regulates cell migration through an interaction with G α13 .