Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression

Keasey, Matthew P.; Kang, Seong Su; Lovins, Chiharu; Hagg, Theo

doi:10.1186/1478-811x-11-35

Cited by 35 publications

(63 citation statements)

References 121 publications

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“…It remains to be determined which pathways downstream of FAK might be involved, but could include the serine kinases JNK1 [22] or ERK [73]. The latter is also activated by HGF [34].…”

Section: Discussionmentioning

confidence: 99%

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Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

et al. 2016

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BackgroundSTAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof.MethodsCultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators. STAT3 null cells were transfected with mutant STAT3 plasmids. Outcome measures included oxygen consumption rate for mitochondrial bioenergetics, Western blotting for protein phosphorylation, mitochondrial membrane potential for mitochondrial integrity, ROS production, and cell counts.ResultsVitronectin-dependent mitochondrial basal respiration, ATP production, and maximum reserve and respiratory capacities were suppressed within 4 h by RGD and αvβ3 integrin antagonist peptides. Conversely, integrin ligands vitronectin, laminin and fibronectin stimulated mitochondrial function. Pharmacological inhibition of FAK completely abolished mitochondrial function within 4 h while FAK siRNA treatments confirmed the specificity of FAK signaling. WT, but not S727A functionally dead mutant STAT3, rescued bioenergetics in cells made null for STAT3 using CRISPR-Cas9. STAT3 inhibition with stattic in whole cells rapidly reduced mitochondrial function and mitochondrial pS727-STAT3. Stattic treatment of isolated mitochondria did not reduce pS727 whereas more was detected upon phosphatase inhibition. This suggests that S727-STAT3 is activated in the cytoplasm and is short-lived upon translocation to the mitochondria. FAK inhibition reduced pS727-STAT3 within mitochondria and reduced mitochondrial function in a non-transcriptional manner, as shown by co-treatment with actinomycin. Treatment with the small molecule bryostatin-1 or hepatocyte growth factor (HGF), which indirectly activate S727-STAT3, preserved mitochondrial function during FAK inhibition, but failed in the presence of the STAT3 inhibitor. FAK inhibition induced loss of mitochondrial membrane potential, which was counteracted by bryostatin, and increased superoxide and hydrogen peroxide production. Bryostatin and HGF reduced the substantial cell death caused by FAK inhibition over a 24 h period.ConclusionThese data suggest that extracellular matrix molecules promote STAT3-dependent mitochondrial function and cell survival through integrin-FAK signaling. We furthermore show a new treatment strategy for cell survival using S727-STAT3 activators.

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“…It remains to be determined which pathways downstream of FAK might be involved, but could include the serine kinases JNK1 [22] or ERK [73]. The latter is also activated by HGF [34].…”

Section: Discussionmentioning

confidence: 99%

“…We recently discovered an integrin signaling pathway that inhibits CNTF expression, involving FAK, JNK and the S727 residue of the transcription factor STAT3 [22]. Depending on phosphorylation of residues S727 or Y705, STAT3 can inhibit or promote nuclear gene expression [23].…”

Section: Introductionmentioning

confidence: 99%

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

et al. 2016

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“…Our previous study showed that integrin-FAK signaling promotes STAT3 phosphorylation specifically on the S727 residue [21]. Here, ER stress induced by TG and TM caused a reduction in phosphorylation of the key Y397 residue of FAK, as early as 24 h (Fig.…”

Section: Resultsmentioning

confidence: 67%

“…We recently identified an FAK-STAT3 pathway that activates the S727 residue of STAT3 [21], and determined that FAK inhibition caused dramatic changes in mitochondrial bioenergetic function [26]. Here, the ER stress-induced loss of pS727-STAT3 coincided with reductions in pFAK.…”

Section: Discussionmentioning

confidence: 99%

“…Integrins prevent apoptosis through FAK-AKT signaling [19] and inhibiting mitochondria-associated bit1 [20]. We discovered a selective integrin signaling pathway that inhibits CNTF expression, involving FAK and the S727 residue of the downstream STAT3 transcription factor [21]. STAT3, when phosphorylated on S727, translocates to the mitochondria instead of the nucleus and plays a major, non-transcriptional role in preserving mitochondrial function [22].…”

Section: Introductionmentioning

confidence: 99%

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Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells

Banerjee

Keasey

Razskazovskiy

et al. 2017

Cellular Signalling

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Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72 h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress.

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Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

Jia

Keasey

Lovins

et al. 2018

Glia

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Astrocyte-derived ciliary neurotrophic factor (CNTF) promotes adult subventricular zone (SVZ) neurogenesis. We found that focal adhesion kinase (FAK) and JNK, but not ERK or P38, repress CNTF in vitro. Here, we defined the FAK-JNK pathway and its regulation of CNTF in mice, and the related leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), which promote stem cell renewal at the expense of neurogenesis. Intrastriatal injection of FAK inhibitor, FAK14, in adult male C57BL/6 mice reduced pJNK and increased CNTF expression in the SVZ-containing periventricular region. Injection of a JNK inhibitor increased CNTF without affecting LIF and IL-6, and increased SVZ proliferation and neuroblast formation. The JNK inhibitor had no effect in CNTF−/− mice, suggesting that JNK inhibits SVZ neurogenesis by repressing CNTF. Inducible deletion of FAK in astrocytes increased SVZ CNTF and neurogenesis, but not LIF and IL-6. Intrastriatal injection of inhibitors suggested that P38 reduces LIF and IL-6 expression, whereas ERK induces CNTF and LIF. Intrastriatal FAK inhibition increased LIF, possibly through ERK, and IL-6 through another pathway that does not involve P38. Systemic injection of FAK14 also inhibited JNK while increasing CNTF, but did not affect P38 and ERK activation, or LIF and IL-6 expression. Importantly, systemic FAK14 increased SVZ neurogenesis in wildtype C57BL/6 and CNTF+/+ mice, but not in CNTF−/− littermates, indicating that it acts by upregulating CNTF. These data show a surprising differential regulation of related cytokines and identify the FAK-JNK-CNTF pathway as a specific target in astrocytes to promote neurogenesis and possibly neuroprotection in neurological disorders.

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Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression

Cited by 35 publications

References 121 publications

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells

Inhibition of astrocyte FAK–JNK signaling promotes subventricular zone neurogenesis through CNTF

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