FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

Zhou, Wenchao; Feng, Xiujing; Wu, Yingjie; Benge, Johannes; Zhang, Zhe; Chen, Zhengjun

doi:10.1038/cr.2009.95

Cited by 25 publications

(22 citation statements)

References 43 publications

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“…FRS2 gene knockout in mice causes lethality due to the interruption of the FGFR signaling pathway (36). FRS2 acts as "a conning center" in FGF signaling mainly because it induces sustained levels of activation of ERK (31,38,39). FGF ligands and their receptors are overexpressed in a variety of cancers, including breast, stomach, prostate, pancreas, bladder, and colon (4-7).…”

Section: Discussionmentioning

confidence: 99%

Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma

Zhang

Chu

et al. 2013

Cancer Research

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Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 and MDM2 in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90% to 100% (9-11 of 11) of DDLS, whereas that of FRS2, CDK4, and MDM2 were observed in 55% (41 of 75), 48% (36 of 75), and 44% (33/75) of clinically diagnosed UHGPS, suggesting that these "UHGPS" may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2-positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma

Zhang

Chu

et al. 2013

Cancer Research

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“…12). FRS2 is an adaptor protein that plays a critical role in fibroblast growth factor receptor signaling (6,28). FRS2 in fibroblast growth factor receptor signaling pathways induces downstream activation of the RAS-MAPK pathway.…”

Section: Cardiomyocyte Autophagymentioning

confidence: 99%

MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy

Higashi

Yamada

Minatoguchi

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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We investigated whether microRNA-145 (miR-145) has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion, followed by 2 days or 2 wk of reperfusion. Control microRNA (control group; 2.5 nmol/kg, n = 10) or miR-145 (miR-145 group, 2.5 nmol/kg, n = 10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR-145 group than in the control group at 2 days and 2 wk post-MI. miR-145 had improved the cardiac function and remodeling at 2 wk post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and downregulated p62/SQSTM1 at 2 days or 2 wk after MI, but not at 4 wk, and activated Akt in the ischemic area at 2 days after MI. miR-145 inhibited the growth of H9c2 cells, accelerated the transition of LC3B I to II, and increased phosphorylated Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2.

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“…To date, FRS2α has been implicated in biological activities regulated by FGF and NGF including cell proliferation and migration, outgrowth of neuritis, and development of various organs and tissues (11,20). Frs2α −/− mice die at E7.0-E7.5 because of multiple developmental problems including abnormal anterior-posterior axis formation, failure of development of the extraembryonic ectoderm, cerebral cortex, eye, carotid body, cardiac outflow tract, prostate, limbs and skeleton, and widespread vascular abnormalities (21).…”

Section: Discussionmentioning

confidence: 99%

The docking protein FRS2α is a critical regulator of VEGF receptors signaling

Chen

Qin²,

Zhuang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Regulation of vascular endothelial growth factor (VEGF) signaling plays a central role in a range of biological processes from embryonic and perinatal vascular development to maintenance of the mature adult vasculature to regulation of various organs function. We report that the intracellular docking protein FRS2α, not hitherto known to be involved in VEGF signaling, plays a critical role in regulation of this process.

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FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway

Cited by 25 publications

References 43 publications

Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma

Amplification of FRS2 and Activation of FGFR/FRS2 Signaling Pathway in High-Grade Liposarcoma

MicroRNA-145 repairs infarcted myocardium by accelerating cardiomyocyte autophagy

The docking protein FRS2α is a critical regulator of VEGF receptors signaling

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