FRS2 Proteins Recruit Intracellular Signaling Pathways by Binding to Diverse Targets on Fibroblast Growth Factor and Nerve Growth Factor Receptors

Ong, Siew Hwa; Guy, Graeme R.; Hadari, Yaron R.; Laks, Shaked; Gotoh, Noriko; Schlessinger, Joseph; Lax, Irit

doi:10.1128/mcb.20.3.979-989.2000

Cited by 322 publications

(290 citation statements)

References 45 publications

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“…FRS2a binds constitutively to FGFR through its PTB domain at the NH 2 terminus and six tyrosine residues at the COOH terminus are phosphorylated by activated FGFR. Once FRS2a is phosphorylated, it recruits adaptor molecules such as Grb2 and Shp2 and relays the signals to the Ras/mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase/Akt pathway (22,23). In addition, FGFR is known to direct cytoskeletal reorganization through regulating small GTPases, although its precise signaling mechanism has not been clarified (24).…”

Section: Introductionmentioning

confidence: 99%

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

Fukai

Yokote²,

Yamanaka³

et al. 2008

Molecular Cancer Therapeutics

128

112

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The Eph receptor tyrosine kinases and their ephrin ligands form a unique cell-cell contact-mediated bidirectional signaling mechanism for regulating cell localization and organization. High expression of Eph receptors in a wide variety of human tumors indicates some roles in tumor progression, which makes these proteins potential targets for anticancer therapy. For this purpose, we did gene expression profiling for 47 surgical specimens of brain tumors including 32 high-grade glioma using a microarray technique. The analysis, focused on the receptor tyrosine kinases, showed that EphA4 mRNA in the tumors was 4-fold higher than in normal brain tissue. To investigate the biological significance of EphA4 overexpression in these tumors, we analyzed EphA4-induced phenotypic changes and the signaling mechanisms using human glioma U251 cells. EphA4 promoted fibroblast growth factor 2-mediated cell proliferation and migration accompanied with enhancement of fibroblast growth factor 2-triggered mitogen-activated protein kinase and Akt phosphorylation. In addition, active forms of Rac1 and Cdc42 increased in the EphA4-overexpressing cells. Furthermore, we found that EphA4 formed a heteroreceptor complex with fibroblast growth factor receptor 1 (FGFR1) in the cells and that the EphA4-FGFR1 complex potentiated FGFR-mediated downstream signaling. Thus, our results indicate that EphA4 plays an important role in malignant phenotypes of glioblastoma by enhancing cell proliferation and migration through accelerating a canonical FGFR signaling pathway. [Mol Cancer Ther 2008;7(9):2768 -78]

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Section: Introductionmentioning

confidence: 99%

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

Fukai

Yokote²,

Yamanaka³

et al. 2008

Molecular Cancer Therapeutics

128

112

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“…Phosphorylation of the docking protein FRS2 recruits and activates the Grb2/Sos1 complex, which then interacts with Ras to activate the MAPK pathway (Kouhara et al, 1997;Ong et al, 2000). This signaling pathway has been shown to contribute to FGFR-mediated cell proliferation and migration (Klint and Claesson-Welsh, 1999;Boilly et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins

2004

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Overexpression of fibroblast growth factor receptor (FGFR) tyrosine kinases has been found in many human breast cancers and has been associated with poor patient prognosis. In order to understand the mechanism by which FGFR mediates breast cancer cell proliferation, we used a low molecular weight compound, PD173074, that selectively inhibits FGFR tyrosine kinase activity and autophosphorylation. This potential anticancer agent caused a G1 growth arrest of MDA-MB-415, MDA-MB-453 and SUM 52 breast cancer cells. Our analyses revealed that FGFR signaling links to the cell cycle machinery via D-type cyclins. PD173074-mediated inhibition of FGFR activity caused downregulation of cyclin D1 and cyclin D2 expression, inhibition of cyclin D/cdk4 activity and, as a consequence, reduction of pRB phosphorylation. Retroviral-mediated ectopic expression of cyclin D1 prevented pRB hypophosphorylation and the cell cycle G1 block in PD173074-treated cells, suggesting a central role for D cyclins in proliferation of FGFR-driven breast cancer cells. The repression of FGFR activity caused downregulation of MAPK in MDA-MB-415 and MDA-MB-453 cells. In SUM 52 cells, both MAPK and PI3K signaling pathways were suppressed. In conclusion, results shown here describe a mechanism by which FGFR promotes proliferation of breast cancer cells.

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“…FRS2 then forms a complex with the tyrosine phosphatase Shp2 and the adapter protein Grb2, which associates with the Ras activator Sos. The FRS2-Grb2-Sos ternary complex then activates the Ras/mitogen-activated protein kinase (MAPK) signaling cascade [1,[3][4][5][6]. PY of FRS2 is also reported to play an important role in PI3 kinase activation through the formation of the FRS2-Grb2-Gab1 complex.…”

Section: Introductionmentioning

confidence: 99%

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

Zhou

Feng

et al. 2009

Cell Res

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FRS2 Proteins Recruit Intracellular Signaling Pathways by Binding to Diverse Targets on Fibroblast Growth Factor and Nerve Growth Factor Receptors

Cited by 322 publications

References 45 publications

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

Blocking of FGFR signaling inhibits breast cancer cell proliferation through downregulation of D-type cyclins

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

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