Src family kinases: Regulation of their activities, levels and identification of new pathways

Ingley, Evan

doi:10.1016/j.bbapap.2007.08.012

Cited by 286 publications

(339 citation statements)

References 78 publications

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“…Inhibition of Lyn showed suppression of microglial activation in an Alzheimer's disease model 80. Phosphorylation at tyrosine 397 (p‐Tyr397‐Lyn) is required for Lyn to perform its functional kinase activity81 to effect downstream proinflammatory pathways 79. Hence our observation of downregulation of p‐Tyr397‐Lyn suggests a possible mechanism by which CN‐105 reduces microglial activation.…”

Section: Discussionmentioning

confidence: 69%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 69%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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“…The tyrosine kinase c-Src plays an important role in cell proliferation, survival, adhesion and migration, which are all processes that are tightly associated with tumor progression (Brown and Cooper, 1996;Ingley, 2008). c-Src is frequently overexpressed and activated in a wide variety of human cancers, suggesting that it actively facilitates tumor progression (Frame, 2002;Ishizawar and Parsons, 2004;Yeatman, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Once activated by extracellular signals such as growth factors and integrins, c-Src acts as a common upstream regulator of multiple oncogenic pathways, including the Ras/MAPK pathway and phosphoinositide 3-kinase pathways (Ingley, 2008), which induce the phenotypic changes characteristic of transformation and malignancy. Mounting evidence has demonstrated the importance of c-Src in cancer progression, but the perturbation of the regulatory system of c-Src signaling during cancer progression remains to be elucidated in detail.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

et al. 2011

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The tyrosine kinase c-Src is upregulated in various human cancers; however, the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. Here we show that downregulation of microRNA (miR)-542-3p is tightly associated with tumor progression via c-Src-related oncogenic pathways. In c-Src-transformed fibroblasts and human cancer cells that overexpress c-Src, miR-542-3p is substantially downregulated, and the ectopic expression of miR-542-3p suppresses tumor growth. We identified the integrin-linked kinase (ILK) as a conserved target of miR-542-3p. ILK upregulation promotes cell adhesion and invasion by activating the integrin-focal adhesion kinase (FAK)/c-Src pathway, and can also contribute to tumor growth via the AKT and glycogen synthase kinase 3b pathways. MiR-542-3p expression is downregulated by the activation of c-Src-related signaling molecules, including epidermal growth factor receptor, K-Ras and Ras/ Raf/mitogen-activated protein kinase/extracellular signalregulated kinase. In human colon cancer tissues, downregulation of miR-542-3p is significantly correlated with the upregulation of c-Src and ILK. Our results suggest that the novel c-Src-miR-542-3p-ILK-FAK circuit plays a crucial role in controlling tumor progression.

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“…This phosphorylation induces a closed conformation and inhibition of the kinase (4)(5)(6)(7). In contrast, trans-autophosphorylation of the activation loop tyrosine (Y416 for chicken Src) is crucial for full kinase activity (8)(9)(10).…”

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confidence: 99%

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Štěpánek

Dráber

Drobek

et al. 2013

The Journal of Immunology

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When a BCR on a mature B cell is engaged by its ligand, the cell becomes activated, and the Ab-mediated immune response can be triggered. The initiation of BCR signaling is orchestrated by kinases of the Src and Syk families. However, the proximal BCR-induced phosphorylation remains incompletely understood. According to a model of sequential activation of kinases, Syk acts downstream of Src family kinases (SFKs). In addition, signaling independent of SFKs and initiated by Syk has been proposed. Both hypotheses lack sufficient evidence from relevant B cell models, mainly because of the redundancy of Src family members and the importance of BCR signaling for B cell development. We addressed this issue by analyzing controlled BCR triggering ex vivo on primary murine B cells and on murine and chicken B cell lines. Chemical and Csk-based genetic inhibitor treatments revealed that SFKs are required for signal initiation and Syk activation. In addition, ligand and anti-BCR Ab–induced signaling differ in their sensitivity to the inhibition of SFKs.

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Src family kinases: Regulation of their activities, levels and identification of new pathways

Cited by 286 publications

References 78 publications

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

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