FGFR1 forms an FRS2-dependent complex with mTOR to regulate smooth muscle marker gene expression

Chen, Pei-Yu; Friesel, Robert

doi:10.1016/j.bbrc.2009.03.040

Cited by 18 publications

(13 citation statements)

References 31 publications

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“…The oncogenic role of FGFR2 in SCC was further confirmed using genetic manipulation of FGFR2. In VSMC's, FGFR/FRS2 complex activates Akt/mTOR signaling to regulate gene expression (50). It is possible that FGFR2 activates mTORC1 and mTORC2 via its interaction with FRS2 and subsequent activation of tumor suppressor PTEN.…”

Section: Discussionmentioning

confidence: 99%

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Khandelwal

Rong

Moore-Medlin

et al. 2016

Cancer Prevention Research

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Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the United States due to high exposure to ultraviolet B (UVB) radiation. In our previous studies, Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling that play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against acute UVB-induced hyperproliferation by targeting the mTOR and FGFR signaling pathways. Pretreatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced cell proliferation, progression and colony formation, mTORC1 and mTORC2 activation, and FGFR2 phosphorylation in the promotion-sensitive JB6 cells epithelial cells.Further, FGFR was critical for UVB-induced mTOR activation, suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pretreated with C3 (15 mg/kg/b.w.) for 2 weeks followed by a single exposure to UVB (180 mj/cm 2 ) significantly attenuated UVB-induced mTORC1, mTORC2, and FGFR2 activation. To further assess the role of FGFR in UVBinduced hyperproliferation, SKH-1 mice were pretreated with AZD4547 (5 mg/kg/b.w.); a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (180 mj/cm 2 ). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyperproliferation. Our studies underscore the importance of FGFR signaling in UVBinduced acute skin changes and the role of FGFR/mTOR signaling in mediating the effects of C3 complex in the pathogenesis of skin cancer. Cancer Prev Res; 9(4); 296-304. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Khandelwal

Rong

Moore-Medlin

et al. 2016

Cancer Prevention Research

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“…A direct link may exist between mTOR and the FGF/FGFR1 axis. It is possible that mTOR may become phosphorylated/activated by direct interaction with FGFR1 and associated signals: in vascular smooth muscle cells mTOR was shown to interact directly with FGFR1 via Fibroblast Growth Factor Receptor Substrate 2 [ 53 ]. Further studies are required to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway

Koleini¹,

Nickel²,

Wang

et al. 2017

Oncotarget

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BackgroundCardiotoxic side effects impose limits to the use of anti-tumour chemotherapeutic drugs such as doxorubicin (Dox). There is a need for cardioprotective strategies to prevent the multiple deleterious effects of Dox. Here, we examined the ability of administered fibroblast growth factor-2 (FGF-2), a cardioprotective protein that is synthesized as high and low molecular weight (Hi-, Lo-FGF-2) isoforms, to prevent Dox-induced: oxidative stress; cell death; lysosome dysregulation; and inactivation of potent endogenous protective pathways, such as the anti-oxidant/detoxification nuclear factor erythroid-2-related factor (Nrf-2), heme oxygenase-1 (HO-1) axis.Methods and ResultsBrief pre-incubation of neonatal rat cardiomyocyte cultures with either Hi- or Lo-FGF-2 reduced the Dox-induced: oxidative stress; apoptotic/necrotic cell death; lysosomal dysregulation; decrease in active mammalian target of Rapamycin (mTOR). FGF-2 isoforms prevented the Dox-induced downregulation of Nrf-2, and promoted robust increases in the Nrf-2-downstream targets including the cardioprotective protein HO-1, and p62/SQSTM1, a multifunctional scaffold protein involved in autophagy. Chloroquine, an autophagic flux inhibitor, caused a further increase in p62/SQSTM1, indicating intact autophagic flux in the FGF-2-treated groups. A selective inhibitor for HO-1, Tin-Protoporphyrin, prevented the FGF-2 protection against cell death. The mTOR inhibitor Rapamycin prevented FGF-2 protection, and blocked the FGF-2 effects on Nrf-2, HO-1 and p62/SQSTM1.ConclusionsIn an acute setting Hi- or Lo-FGF-2 protect cardiomyocytes against multiple Dox-induced deleterious effects, by a mechanism dependent on preservation of mTOR activity, Nrf-2 levels, and the upregulation of HO-1. Preservation/activation of endogenous anti-oxidant/detoxification defences by FGF-2 is a desirable property in the setting of Dox-cardiotoxicity.

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“…3 , 4 ). This atrophy is a consequence of hypogonadotropic hypogonadism [20,21] . Furthermore, low number of germ cells and particularly impaired germ cell differentiation is a further evidence of impaired gonadal maturation after birth, also denominated mini-puberty ( fig.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, low number of germ cells and particularly impaired germ cell differentiation is a further evidence of impaired gonadal maturation after birth, also denominated mini-puberty ( fig. 3 , 4 ) [20,21] . Furthermore, FGFR1 affects the proliferation and migration of vascular smooth muscle cells [22] and is involved in myoblast proliferation and differentiation [23] .…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of FGFR1, SOS1, RAF1 Genes in Cryptorchidism

Hadziselimovic¹,

Geyter

Demougin

et al. 2010

Urol Int

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Background: In recent years, several genes were found to be involved in the process of epididymo-testicular descent, the most frequently cited ones include INSL3, HOXA10, GNRHR, and KAL1. In this study, we analyzed the differences in gene expression profiles between cryptorchid and descended testes. In particular, we analyzed expression of all recently published genes known to be associated with undescended testis. Patients and Methods: Twenty-two testicular biopsies from 18 boys were analyzed. We analyzed gene expression in 16 cryptorchid and 6 descended testes using Affymetrix Human Genome U133 Plus 2.0 GeneChips, and validated the results with qPCR. Results: 3,688 transcripts were differentially expressed with an adjusted p value of <0.05 and a change of at least 1.5-fold. The list contained 1,866 downregulated and 1,822 upregulated transcripts in the cryptorchid testes. A novel observation in our study was that the fibroblast growth factor receptor 1 gene (FGFR1) and its mediators SOS1 and RAF1 were expressed less in undescended testes. Conclusion: Based on our results, it is possible that a subtle dysfunction (expression) of the FGFR1, SOS1 and RAF1 genes is involved in the development of the most common male reproductive tract disorder – unilateral or bilateral cryptorchidism.

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FGFR1 forms an FRS2-dependent complex with mTOR to regulate smooth muscle marker gene expression

Cited by 18 publications

References 31 publications

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Fibroblast growth factor-2-mediated protection of cardiomyocytes from the toxic effects of doxorubicin requires the mTOR/Nrf-2/HO-1 pathway

Decreased Expression of <i>FGFR1</i>, <i>SOS1</i>, <i>RAF1</i> Genes in Cryptorchidism

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