FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion

Stanicka, Joanna; Rieger, Leonie; O'Shea, Sandra; Cox, Órla T.; Coleman, Michael F.; O’Flanagan, Ciara H.; Addario, Barbara; McCabe, Nuala; Kennedy, Richard D.; O’Connor, Rosemary

doi:10.1038/s41388-017-0113-z

Cited by 23 publications

(26 citation statements)

References 51 publications

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“…If this is the case for human cancers, upregulation of the c‐Src‐mediated pathway observed in various human cancers could be induced through a positive feedback loop involving miR‐129‐1‐3p and c‐Src that can be initiated by growth factor and integrin stimuli. Furthermore, recent work showed that c‐Src is also activated by Fer, suggesting that c‐Src activation is maintained by its substrate . Thus, upregulation of c‐Src might further amplify the positive feedback loop mediated by direct regulation of c‐Src‐related protein levels by miR‐129‐1‐3p and regulation of c‐Src kinase activity by Fer, thereby promoting tumor malignancy mediated by c‐Src activation.…”

Section: Discussionmentioning

confidence: 99%

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

et al. 2020

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MicroRNAs (miRNAs) fine-tune cellular signaling by regulating expression of signaling proteins, and aberrant expression of miRNAs is observed in many cancers. The tyrosine kinase c-Src is upregulated in various human cancers, but the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. In previous investigations of miRNA-mediated control of c-Src-related oncogenic pathways, we identified miRNAs that were downregulated in association with c-Src transformation and uncovered the signaling networks by predicting their target genes, which might act cooperatively to control tumor progression. Here, to further elucidate the process of cell transformation driven by c-Src, we analyzed the expression profiles of miRNAs in a doxycycline-inducible Src expression system. We found that miRNA (miR)-129-1-3p was downregulated in the early phase of c-Src-induced cell transformation, and that reexpression of miR-129-1-3p disrupted c-Src-induced cell transformation. In addition, miR-129-1-3p downregulation was tightly associated with tumor progression in human colon cancer cells/tissues. Expression of miR-129-1-3p in human colon cancer cells caused morphological changes and suppressed tumor growth, cell adhesion, and invasion. We also identified c-Src and its critical substrate Fer, and c-Yes, a member of the Src family of kinases, as novel targets of miR-129-1-3p. Furthermore, we found that miR-129-1-3p-mediated regulation of c-Src/Fer and c-Yes is important for controlling cell adhesion and invasion. Downregulation of miR-129-1-3p by early activation of c-Src increases expression of these target genes and synergistically promotes c-Src-related oncogenic signaling. Thus, c-Src-miR-129-1-3p circuits serve as critical triggers for tumor progression in many human cancers that harbor upregulation of c-Src. K E Y W O R D Scolon cancer, malignancy, microRNA, signaling, Src | 419 OKUZAKI et Al.

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Section: Discussionmentioning

confidence: 99%

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

et al. 2020

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“…In addition, we showed that cell attachment to normal cells is inhibited in cells highly expressing IRS-1. It was reported that integrin and cadherin were bound to IRS-1 and the IGF-I receptor (24)(25)(26), and these molecules play roles in cell-cell or cell-extracellular matrix binding (27,28). Moreover, Canonici et al explained that IGF-I modulates association between IGF-I receptor, αv integrin and E-cadherin (29).…”

Section: Discussionmentioning

confidence: 99%

Myoblasts With Higher IRS-1 Levels Are Eliminated From the Normal Cell Layer During Differentiation

et al. 2020

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Insulin receptor substrate (IRS)-1 is a major substrate of insulin-like growth factor (IGF)-I receptors. It is well-known that IGF-I and II play essential roles in myogenesis progression. Herein, we report an unexpected phenomenon that IRS-1-overexpressing L6 myoblasts are eliminated from normal cell layers at the beginning of differentiation. Initially, the IRS protein level and apoptosis were examined during myogenic differentiation in L6 myoblasts. We found that the IRS-1 protein level decreased, whereas active caspase 3 increased around 1 day after induction of differentiation. The addition of a pan-caspase inhibitor, Z-VAD-FMK, inhibited differentiation-induced suppression of the IRS-1 protein level. Apoptosis was not enhanced in L6 myoblasts stably expressing high levels of IRS-1 (L6-IRS-1). However, when L6-IRS-1 was cultured with control cells (L6-mock), we observed that L6-IRS-1 was eliminated from the cell layer. We have recently reported that, in L6-IRS-1, internalization of the IGF-I receptor was delayed and IGF signal activation was sustained for a longer period than in L6-mock. When cells stably expressing IRS-1 3YA mutant, which could not maintain the IGF signals, were cultured with normal cells, elimination from the cell layer was not detected. These data suggested that the high level of IRS-1 in myoblasts induces elimination from the cell layer due to abnormal sustainment of IGF-I receptor activation.

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“…Notably, we identified FER as its own substrate since the Tyr402 residue of the kinase is known to be auto-phosphorylated (16). We also identified IGF-1R, a key tyrosine kinase receptor in regulating cancer cell survival, proliferation, and motility (24). In addition, a number of unreported genes were also listed, including XPO1 and IPO4 (cytoplasm-nucleus shuttle (25,26)), SLC25A5, SLC25A6 and SLC3A2 (ADP/ATP transportation from mitochondria to cytoplasm, as well as heteromeric amino acid and polyamine transportation (27,28)), and UBA1 and UBE3C (ubiquitin-proteasome degradation (29,30)).…”

Section: Mass Spectrometry Analysis Identified Irs4 As a Novel Substrmentioning

confidence: 95%

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

Zhang

Xiong

Zhu

et al. 2020

Preprint

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Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time and space dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer. Knockdown of the kinase attenuates metastatic phenotypes in tumor cells. Here we employed mass spectrometry and biochemical approaches to identify IRS4 as a novel substrate of FER. Using a proximity-based tagging system, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI-3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4, delayed tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate regulatory mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

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FES-related tyrosine kinase activates the insulin-like growth factor-1 receptor at sites of cell adhesion

Cited by 23 publications

References 51 publications

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

Myoblasts With Higher IRS-1 Levels Are Eliminated From the Normal Cell Layer During Differentiation

FER-mediated tyrosine phosphorylation and PIK3R2/p85β recruitment on IRS4 promotes the PI3K-AKT signaling pathway and tumorigenesis in ovarian cancer

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