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Angela L Tyner - One of the best experts on this subject based on the ideXlab platform.
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abstract 225 protein tyrosine kinase 6 directly phosphorylates p130 crk associated substrate to promote peripheral Adhesion Complex formation and cell migration
Cancer Research, 2012Co-Authors: Yu Zheng, Angela L TynerAbstract:Protein tyrosine kinase 6 (PTK6) is a nonmyristoylated intracellular tyrosine kinase evolutionarily related to Src kinases. Aberrant PTK6 expression and intracellular localization have been detected in human prostate tumors. Although the majority of total PTK6 is localized within the cytoplasm of PC3 cells, a human prostate cancer cell line, we found that the activated pool of PTK6 phosphorylated on tyrosine residue 342 is localized at the membrane. Ectopic expression of membrane targeted PTK6 leads to enhanced activation of PTK6 at the membrane and the formation of 6 to 12 striking focal Adhesion-like Complexes localized at the periphery of each cell, termed peripheral Adhesion Complexes. Using confocal microscopy, we show that p130 CRK-Associated Substrate (p130CAS), FAK, Paxillin and Vinculin, as well as increased levels of tyrosine phosphorylated proteins and active PTK6 are localized within the induced peripheral Adhesion Complexes. We determined that peripheral Adhesion Complex formation is dependent upon PTK6 tyrosine kinase activity. We demonstrate that p130CAS is a novel direct substrate of PTK6 that works as a crucial adapter protein in PTK6 mediated formation of peripheral Adhesion Complexes. We found that activation of ERK5 signaling downstream of p130CAS is indispensible for this process. Knockdown of p130CAS attenuates oncogenic signaling induced by membrane targeted PTK6, including ERK5 and AKT activation. We show that formation of peripheral Adhesion Complexes is associated with enhanced cell migration. PC3 cells expressing membrane targeted PTK6 exhibit increased migratory ability, which can be impaired by knockdown of p130CAS or ERK5. In contrast, knockdown of endogenous PTK6 in PC3 cells reduces cell migration, which is accompanied with decreased phosphorylation of p130CAS and ERK5. Our study reveals a novel function for PTK6 at the plasma membrane, and suggests that a PTK6-p130CAS-ERK5 signaling cascade plays an important role in cancer cell migration and invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 225. doi:1538-7445.AM2012-225
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protein tyrosine kinase 6 promotes peripheral Adhesion Complex formation and cell migration by phosphorylating p130 crk associated substrate
Journal of Biological Chemistry, 2012Co-Authors: Yu Zheng, John M Asara, Angela L TynerAbstract:Protein-tyrosine kinase 6 (PTK6) is a non-myristoylated intracellular tyrosine kinase evolutionarily related to Src kinases. Aberrant PTK6 expression and intracellular localization have been detected in human prostate tumors. In the PC3 prostate cancer cell line, the pool of endogenous activated PTK6, which is phosphorylated on tyrosine residue 342, is localized at the membrane. Expression of ectopic membrane-targeted PTK6 led to dramatic morphology changes and formation of peripheral Adhesion Complexes in PC3 cells. Peripheral Adhesion Complex formation was dependent upon PTK6 kinase activity. We demonstrated that p130 CRK-associated substrate (p130CAS) is a novel direct substrate of PTK6, and it works as a crucial adapter protein in inducing peripheral Adhesion Complexes. Activation of ERK5 downstream of p130CAS was indispensable for this process. Knockdown of endogenous PTK6 led to reduced cell migration and p130CAS phosphorylation, whereas knockdown of p130CAS attenuated oncogenic signaling induced by membrane-targeted PTK6, including ERK5 and AKT activation. Expression of membrane-targeted PTK6 promoted cell migration, which could be impaired by knockdown of p130CAS or ERK5. Our study reveals a novel function for PTK6 at the plasma membrane and suggests that the PTK6-p130CAS-ERK5 signaling cascade plays an important role in cancer cell migration and invasion.
Yu Zheng - One of the best experts on this subject based on the ideXlab platform.
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abstract 225 protein tyrosine kinase 6 directly phosphorylates p130 crk associated substrate to promote peripheral Adhesion Complex formation and cell migration
Cancer Research, 2012Co-Authors: Yu Zheng, Angela L TynerAbstract:Protein tyrosine kinase 6 (PTK6) is a nonmyristoylated intracellular tyrosine kinase evolutionarily related to Src kinases. Aberrant PTK6 expression and intracellular localization have been detected in human prostate tumors. Although the majority of total PTK6 is localized within the cytoplasm of PC3 cells, a human prostate cancer cell line, we found that the activated pool of PTK6 phosphorylated on tyrosine residue 342 is localized at the membrane. Ectopic expression of membrane targeted PTK6 leads to enhanced activation of PTK6 at the membrane and the formation of 6 to 12 striking focal Adhesion-like Complexes localized at the periphery of each cell, termed peripheral Adhesion Complexes. Using confocal microscopy, we show that p130 CRK-Associated Substrate (p130CAS), FAK, Paxillin and Vinculin, as well as increased levels of tyrosine phosphorylated proteins and active PTK6 are localized within the induced peripheral Adhesion Complexes. We determined that peripheral Adhesion Complex formation is dependent upon PTK6 tyrosine kinase activity. We demonstrate that p130CAS is a novel direct substrate of PTK6 that works as a crucial adapter protein in PTK6 mediated formation of peripheral Adhesion Complexes. We found that activation of ERK5 signaling downstream of p130CAS is indispensible for this process. Knockdown of p130CAS attenuates oncogenic signaling induced by membrane targeted PTK6, including ERK5 and AKT activation. We show that formation of peripheral Adhesion Complexes is associated with enhanced cell migration. PC3 cells expressing membrane targeted PTK6 exhibit increased migratory ability, which can be impaired by knockdown of p130CAS or ERK5. In contrast, knockdown of endogenous PTK6 in PC3 cells reduces cell migration, which is accompanied with decreased phosphorylation of p130CAS and ERK5. Our study reveals a novel function for PTK6 at the plasma membrane, and suggests that a PTK6-p130CAS-ERK5 signaling cascade plays an important role in cancer cell migration and invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 225. doi:1538-7445.AM2012-225
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protein tyrosine kinase 6 promotes peripheral Adhesion Complex formation and cell migration by phosphorylating p130 crk associated substrate
Journal of Biological Chemistry, 2012Co-Authors: Yu Zheng, John M Asara, Angela L TynerAbstract:Protein-tyrosine kinase 6 (PTK6) is a non-myristoylated intracellular tyrosine kinase evolutionarily related to Src kinases. Aberrant PTK6 expression and intracellular localization have been detected in human prostate tumors. In the PC3 prostate cancer cell line, the pool of endogenous activated PTK6, which is phosphorylated on tyrosine residue 342, is localized at the membrane. Expression of ectopic membrane-targeted PTK6 led to dramatic morphology changes and formation of peripheral Adhesion Complexes in PC3 cells. Peripheral Adhesion Complex formation was dependent upon PTK6 kinase activity. We demonstrated that p130 CRK-associated substrate (p130CAS) is a novel direct substrate of PTK6, and it works as a crucial adapter protein in inducing peripheral Adhesion Complexes. Activation of ERK5 downstream of p130CAS was indispensable for this process. Knockdown of endogenous PTK6 led to reduced cell migration and p130CAS phosphorylation, whereas knockdown of p130CAS attenuated oncogenic signaling induced by membrane-targeted PTK6, including ERK5 and AKT activation. Expression of membrane-targeted PTK6 promoted cell migration, which could be impaired by knockdown of p130CAS or ERK5. Our study reveals a novel function for PTK6 at the plasma membrane and suggests that the PTK6-p130CAS-ERK5 signaling cascade plays an important role in cancer cell migration and invasion.
Thomas Walz - One of the best experts on this subject based on the ideXlab platform.
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an ensemble of flexible conformations underlies mechanotransduction by the cadherin catenin Adhesion Complex
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: M Bush, B M Alhanshali, Shuo Qian, Iain D Nicholl, Tsutomu Matsui, Thomas M Weiss, William T Heller, Christopher B. Stanley, Thomas WalzAbstract:The cadherin–catenin Adhesion Complex is the central component of the cell–cell Adhesion adherens junctions that transmit mechanical stress from cell to cell. We have determined the nanoscale structure of the adherens junction Complex formed by the α-catenin•β-catenin•epithelial cadherin cytoplasmic domain (ABE) using negative stain electron microscopy, small-angle X-ray scattering, and selective deuteration/small-angle neutron scattering. The ABE Complex is highly pliable and displays a wide spectrum of flexible structures that are facilitated by protein-domain motions in α- and β-catenin. Moreover, the 107-residue intrinsically disordered N-terminal segment of β-catenin forms a flexible “tongue” that is inserted into α-catenin and participates in the assembly of the ABE Complex. The unanticipated ensemble of flexible conformations of the ABE Complex suggests a dynamic mechanism for sensitivity and reversibility when transducing mechanical signals, in addition to the catch/slip bond behavior displayed by the ABE Complex under mechanical tension. Our results provide mechanistic insight into the structural dynamics for the cadherin–catenin Adhesion Complex in mechanotransduction.
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extracellular architecture of the syg 1 syg 2 Adhesion Complex instructs synaptogenesis
Cell, 2014Co-Authors: Engin Ozkan, Thomas Walz, Poh Hui Chia, Ruiqi Rachel Wang, Natalia Goriatcheva, Dominika Borek, Zbyszek Otwinowski, Kang Shen, Christopher K GarciaAbstract:Summary SYG-1 and SYG-2 are multipurpose cell Adhesion molecules (CAMs) that have evolved across all major animal taxa to participate in diverse physiological functions, ranging from synapse formation to formation of the kidney filtration barrier. In the crystal structures of several SYG-1 and SYG-2 orthologs and their Complexes, we find that SYG-1 orthologs homodimerize through a common, bispecific interface that similarly mediates an unusual orthogonal docking geometry in the heterophilic SYG-1/SYG-2 Complex. C. elegans SYG-1's specification of proper synapse formation in vivo closely correlates with the heterophilic Complex affinity, which appears to be tuned for optimal function. Furthermore, replacement of the interacting domains of SYG-1 and SYG-2 with those from CAM Complexes that assume alternative docking geometries or the introduction of segmental flexibility compromised synaptic function. These results suggest that SYG extracellular Complexes do not simply act as "molecular velcro" and that their distinct structural features are important in instructing synaptogenesis. PaperFlick
Natasha Kyprianou - One of the best experts on this subject based on the ideXlab platform.
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talin1 promotes tumor invasion and metastasis via focal Adhesion signaling and anoikis resistance
Cancer Research, 2010Co-Authors: Shinichi Sakamoto, Richard O Mccann, Rajiv Dhir, Natasha KyprianouAbstract:Talin1 is a focal Adhesion Complex protein that regulates integrin interactions with ECM. This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo . Talin1 overexpression enhanced prostate cancer cell Adhesion, migration, and invasion by activating survival signals and conferring resistance to anoikis. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo . Talin1-regulated cell survival signals via phosphorylation of focal Adhesion Complex proteins, such as focal Adhesion kinase and Src, and downstream activation of AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 immunoreactivity directly correlated with prostate tumor progression to metastasis in the transgenic adenocarcinoma mouse prostate mouse model. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared with primary prostate tumors ( P a ) a therapeutic significance of disrupting talin1 signaling/focal Adhesion interactions in targeting metastatic prostate cancer and ( b ) a potential value for talin1 as a marker of tumor progression to metastasis. Cancer Res; 70(5); 1885–95
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talin1 promotes tumor invasion and metastasis via focal Adhesion signaling and anoikis resistance
Cancer Research, 2010Co-Authors: Shinichi Sakamoto, Richard O Mccann, Rajiv Dhir, Natasha KyprianouAbstract:Talin1 is a focal Adhesion Complex protein that regulates integrin interactions with ECM. This study investigated the significance of talin1 in prostate cancer progression to metastasis in vitro and in vivo. Talin1 overexpression enhanced prostate cancer cell Adhesion, migration, and invasion by activating survival signals and conferring resistance to anoikis. ShRNA-mediated talin1 loss led to a significant suppression of prostate cancer cell migration and transendothelial invasion in vitro and a significant inhibition of prostate cancer metastasis in vivo. Talin1-regulated cell survival signals via phosphorylation of focal Adhesion Complex proteins, such as focal Adhesion kinase and Src, and downstream activation of AKT. Targeting AKT activation led to a significant reduction of talin1-mediated prostate cancer cell invasion. Furthermore, talin1 immunoreactivity directly correlated with prostate tumor progression to metastasis in the transgenic adenocarcinoma mouse prostate mouse model. Talin1 profiling in human prostate specimens revealed a significantly higher expression of cytoplasmic talin1 in metastatic tissue compared with primary prostate tumors (P < 0.0001). These findings suggest (a) a therapeutic significance of disrupting talin1 signaling/focal Adhesion interactions in targeting metastatic prostate cancer and (b) a potential value for talin1 as a marker of tumor progression to metastasis.
Massimo Pignatelli - One of the best experts on this subject based on the ideXlab platform.
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e cadherin catenin cell cell Adhesion Complex and human cancer
British Journal of Surgery, 2002Co-Authors: Bas P L Wijnhoven, Winand N M Dinjens, Massimo PignatelliAbstract:Background The E-cadherin–catenin Complex plays a crucial role in epithelial cell–cell Adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this Complex results in loss of intercellular Adhesion, with possible consequent cell transformation and tumour progression. Recently, much progress has been made in understanding the interaction between the different components of this protein Complex and how this cell–cell Adhesion Complex is modulated in cancer cells. Methods This is an update of the role of the E-cadherin–catenin Complex in human cancers. It emphasizes new features and the possible role of the Complex in clinical practice, discussed in the light of 165 references obtained from the Medline database from 1995 to 1999. Results More evidence is now appearing to suggest that disturbance in protein–protein interaction in the E-cadherin–catenin Adhesion Complex is one of the main events in the early and late steps of cancer development. An inverse correlation is found between expression of the E-cadherin–catenin Complex and the invasive behaviour of tumour cells. Therefore, E-cadherin–catenin may become a significant prognostic marker for tumour behaviour. Besides its role in establishing tight cell–cell Adhesion, β- catenin plays a major role in cell signalling and promotion of neoplastic growth. This suggests its dual role as a tumour suppressor and as an oncogene in human cancers. Conclusion Recent developments show that the E-cadherin–catenin Complex is more than a ‘sticky molecular Complex’. Further studies may yield greater insight into the early molecular interactions critical to the initiation and progression of tumours. This should aid the development of novel strategies for both prevention and treatment of cancer. © 2000 British Journal of Surgery Society Ltd