Characterization of the interaction between lysyl‐tRNA synthetase and laminin receptor by NMR

Cho, Hye Young; Mushtaq, Ameeq Ul; Lee, Jin Young; Kim, Dae Gyu; Seok, Min Sook; Jang, Min-Kyung; Han, Byung Woo; Kim, Sung Hoon; Jeon, Young Ho

doi:10.1016/j.febslet.2014.06.048

Cited by 15 publications

(9 citation statements)

References 30 publications

(54 reference statements)

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“…WFS1 encode for a protein participating in the regulation of cellular Ca 2+ homeostasis. Finally, KARS derived protein is known to interact with laminin receptor on the cell surface and catalyze specific attachment of amino-acid to its cognate tRNA [ 57 ]. The remaining eleven proteins were identified for the first time in SL pericytes.…”

Section: Resultsmentioning

confidence: 99%

In vitro gentamicin exposure alters caveolae protein profile in cochlear spiral ligament pericytes

et al. 2018

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BackgroundThe aminoglycoside antibiotic gentamicin is an ototoxic drug and has been used experimentally to investigate cochlear damage induced by noise.We have investigated the changes in the protein profile associated with caveolae in gentamicin treated and untreated spiral ligament (SL) pericytes, specialized cells in the blood labyrinth barrier of the inner ear microvasculature. Pericytes from various microvascular beds express caveolae, protein and cholesterol rich microdomains, which can undergo endocytosis and transcytosis to transport small molecules in and out the cells. A different protein profile in transport-specialized caveolae may induce pathological changes affecting the integrity of the blood labyrinth barrier and ultimately contributing to hearing loss.MethodCaveolae isolation from treated and untreated cells is achieved through ultracentrifugation of the lysates in discontinuous gradients. Mass spectrometry (LC-MS/MS) analysis identifies the proteins in the two groups. Proteins segregating with caveolae isolated from untreated SL pericytes are then compared to caveolae isolated from SL pericytes treated with the gentamicin for 24 h. Data are analyzed using bioinformatic tools.ResultsThe caveolae proteome in gentamicin treated cells shows that 40% of total proteins are uniquely associated with caveolae during the treatment, and 15% of the proteins normally associated with caveolae in untreated cell are suppressed. Bioinformatic analysis of the data shows a decreased expression of proteins involved in genetic information processing, and an increase in proteins involved in metabolism, vesicular transport and signal transduction in gentamicin treated cells. Several Rab GTPases proteins, ubiquitous transporters, uniquely segregate with caveolae and are significantly enriched in gentamicin treated cells.ConclusionWe report that gentamicin exposure modifies protein profile of caveolae from SL pericytes. We identified a pool of proteins which are uniquely segregating with caveolae during the treatment, mainly participating in metabolic and biosynthetic pathways, in transport pathways and in genetic information processing. Finally, we show for the first time proteins associated with caveolae SL pericytes linked to nonsyndromic hearing loss.Electronic supplementary materialThe online version of this article (10.1186/s12953-018-0132-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

In vitro gentamicin exposure alters caveolae protein profile in cochlear spiral ligament pericytes

et al. 2018

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“…Cell surface interactions are one of the most important events for the initiation of biological responses. KRS was shown to interact with the 67-kDa laminin receptor (67LR), leading to cancer cell migration during metastasis (11,24). As 67LR has been reported to be expressed in DCs (25), and the expression of 67LR might confer different roles in DCs and cancer cells, we examined whether 67LR was involved in the KRS-induced DC maturation and activation.…”

Section: Discussionmentioning

confidence: 99%

Lysyl–Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-κB Pathways, Strongly Contributing to Enhanced Th1 Cell Responses

Lim

Jung

Lee

et al. 2018

The Journal of Immunology

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In addition to essential roles in protein synthesis, lysyl-tRNA synthetase (KRS) is secreted to trigger a proinflammatory function that induces macrophage activation and TNF-a secretion. KRS has been associated with autoimmune diseases such as polymyositis and dermatomyositis. In this study, we investigated the immunomodulatory effects of KRS on bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and subsequent polarization of Th cells and analyzed the underlying mechanisms. KRS-treated DCs increased the expression of cell surface molecules and proinflammatory cytokines associated with DC maturation and activation. Especially, KRS treatment significantly increased production of IL-12, a Th1-polarizing cytokine, in DCs. KRS triggered the nuclear translocation of the NF-kB p65 subunit along with the degradation of IkB proteins and the phosphorylation of MAPKs in DCs. Additionally, JNK, p38, and ERK inhibitors markedly recovered the degradation of IkB proteins, suggesting the involvement of MAPKs as the upstream regulators of NF-kB in the KRS-induced DC maturation and activation. Importantly, KRS-treated DCs strongly increased the differentiation of Th1 cells when cocultured with CD4 + T cells. The addition of anti-IL-12-neutralizing Ab abolished the secretion of IFN-g in the coculture, indicating that KRS induces Th1 cell response via DC-derived IL-12. Moreover, KRS enhanced the OVA-specific Th1 cell polarization in vivo following the adoptive transfer of OVA-pulsed DCs. Taken together, these results indicated that KRS effectively induced the maturation and activation of DCs through MAPKs/NF-kB-signaling pathways and favored DC-mediated Th1 cell response.

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“…CFL1 is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. Increased phosphorylation of this protein by LIM kinase aids in Rho-induced reorganization of the actin cytoskeleton [18]. CFL1 is an actin-severing protein that creates free barbed ends in the actin-severing process.…”

Section: Discussionmentioning

confidence: 99%

“…This synergy between CFL1 severing activity and Arp2/3-generated dendritic nucleation resulting in the formation of stable invadopods and a directional migration, linking CFL1and ARP2/3, through RhoG, to tumor cell invasion [15, 19]. CFL1 pathway was previously related with metastases processes in breast cancer [18]. Furthermore, DYNRBL1 is required for TGFb1 secretion.…”

Section: Discussionmentioning

confidence: 99%

“…By last, lysyl-tRNA synthetase (KARS), also known by KRS, was recently shown to induce cancer cell migration through its interaction with the 67-kDa laminin receptor (67LR) who binds laminin on ECM. The interaction of KRS with 67LR enhances the membrane stability of 67LR, which in turn results in an increase laminin-dependent cell migration in metastasis [18]. KARS, causes incomplete epithelial-mesenchymal transition and ineffective cell-extracellular matrix adhesion for migration [22].…”

Section: Discussionmentioning

confidence: 99%

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Bayesian Networks established functional differences between breast cancer subtypes

Trilla-Fuertes

Zapater-Moros

Gámez‐Pozo

et al. 2018

Preprint

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Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which has a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 106 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as metastasis or proliferation between breast cancer subtypes, including our new subtype TN-like. In addition, one of the components, mainly related with metastasis, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.Author SummaryBreast cancer classification in the clinical practice is defined by three biomarkers (estrogen receptor, progesterone receptor and HER2) into hormone receptor positive, HER2+ and triple negative breast cancer (TNBC). Our group recently described a new ER+ subtype with molecular characteristics and prognosis similar to TNBC. In this study we propose a mathematical method, the Bayesian networks, as a useful tool to study protein interactions and differential biological processes in breast cancer subtypes, characterizing differences in relevant processes such as proliferation or metastasis and associated them with patient prognosis.

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Characterization of the interaction between lysyl‐tRNA synthetase and laminin receptor by NMR

Cited by 15 publications

References 30 publications

In vitro gentamicin exposure alters caveolae protein profile in cochlear spiral ligament pericytes

In vitro gentamicin exposure alters caveolae protein profile in cochlear spiral ligament pericytes

Lysyl–Transfer RNA Synthetase Induces the Maturation of Dendritic Cells through MAPK and NF-κB Pathways, Strongly Contributing to Enhanced Th1 Cell Responses

Bayesian Networks established functional differences between breast cancer subtypes

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