Insulin Receptor Substrate-4 Binds to Slingshot-1 Phosphatase and Promotes Cofilin Dephosphorylation

Homma, Yuta; Kanno, Shin Ichiro; Sasaki, Kento; Nishita, Michiru; Yasui, Akira; Asano, Tomohiko; Ohashi, Kazumasa; Mizuno, Kensaku

doi:10.1074/jbc.m114.565945

Cited by 21 publications

(15 citation statements)

References 34 publications

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“…PI3K is involved in insulin-induced or AngII-induced activation of SSH1 in vitro (38–40). Therefore, we treated Fbln4 SMKO mice with the PI3K inhibitors Wortmannin or LY294002 from P7 to P30 and examined the formation of aneurysms at P30.…”

Section: Resultsmentioning

confidence: 99%

Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

et al. 2015

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Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4SMKO mice with a smooth muscle cell-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4SMKO aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 phosphatase (SSH1), an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident and the abundance of early growth response-1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinsitide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1 and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.

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Section: Resultsmentioning

confidence: 99%

Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

et al. 2015

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“…Similarly, crenolanib is a potent TKI with strongest affinity for PDGF-a and -b receptors and FLT3 (34). Stimulation of several different RTKs and G protein-coupled receptors, for example, insulin receptor, formyl peptide receptor 1, and PDGFR-b, promotes cofilin activity via activation of SSH1/2 to generate rapid turnover of actin filaments in different cell types (42,(49)(50)(51). Accordingly, although PDGFR-b depletion did not affect cofilin regulation, we corroborate that stimulation of U2OS cells with PDGF-BB decreases overall cofilin phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization

et al. 2016

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Centrosome amplification is a hallmark of virtually all types of cancers, including solid tumors and hematologic malignancies. Cancer cells with extra centrosomes use centrosome clustering (CC) to allow for successful division. Because normal cells do not rely on this mechanism, CC is regarded as a promising target to selectively eradicate cells harboring supernumerary centrosomes. To identify novel inhibitors of CC, we developed a cell-based high-throughput screen that reports differential drug cytotoxicity for isogenic cell populations with different centrosome contents. We identified CP-673451 and crenolanib, two chemically related compounds originally developed for the inhibition of platelet-derived growth factor receptor β (PDGFR-β), as robust inhibitors of CC with selective cytotoxicity for cells with extra centrosomes. We demonstrate that these compounds induce mitotic spindle multipolarity by activation of the actin-severing protein cofilin, leading to destabilization of the cortical actin network, and provide evidence that this activation is dependent on slingshot phosphatases 1 and 2 but unrelated to PDGFR-β inhibition. More specifically, we found that although both compounds attenuated PDGF-BB-induced signaling, they significantly enhanced the phosphorylation of PDGFR-β downstream effectors, Akt and MEK, in almost all tested cancer cell lines under physiologic conditions. In summary, our data reveal a novel mechanism of CC inhibition depending on cofilin-mediated cortical actin destabilization and identify two clinically relevant compounds interfering with this tumor cell-specific target. Cancer Res; 76(22); 6690-700. ©2016 AACR.

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“…3c ). The effect of IRS4 on Akt activation has been described previously for various cancer cell lines, fibroblasts, myeloid progenitor cells, HepG2 and HEK293T cells 6 , 7 , 32 – 35 . Here, we demonstrate the link between IRS4 and Akt signalling in muscle precursor cells.…”

Section: Resultsmentioning

confidence: 74%

IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation

Dörpholz

Murgai

Jatzlau

et al. 2017

Sci Rep

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Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator of BMP signal transduction and provide molecular insights how it integrates into the signalling pathway. We found that IRS4 interacts with the BMP receptor BMPRII and specifically targets Smad1 for proteasomal degradation consequently leading to repressed BMP/Smad signalling in C2C12 myoblasts while concomitantly activating the PI3K/Akt axis. IRS4 is present in human and primary mouse myoblasts, the expression increases during myogenic differentiation but is downregulated upon final commitment coinciding with Myogenin expression. Functionally, IRS4 promotes myogenesis in C2C12 cells, while IRS4 knockdown inhibits differentiation of myoblasts. We propose that IRS4 is particularly critical in the myoblast stage to serve as a molecular switch between BMP/Smad and Akt signalling and to thereby control cell commitment. These findings provide profound understanding of the role of BMP signalling in early myogenic differentiation and open new ways for targeting the BMP pathway in muscle regeneration.

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Insulin Receptor Substrate-4 Binds to Slingshot-1 Phosphatase and Promotes Cofilin Dephosphorylation

Cited by 21 publications

References 34 publications

Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice

Pharmacological Inhibition of Centrosome Clustering by Slingshot-Mediated Cofilin Activation and Actin Cortex Destabilization

IRS4, a novel modulator of BMP/Smad and Akt signalling during early muscle differentiation

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