Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification.
Fibroblast growth factor receptors (FGFR) are cell surface tyrosine kinases that function in cell proliferation and differentiation. Aberrant FGFR signaling occurs in diverse cancers due to gene amplification, but the associated oncogenic mechanisms are poorly understood. Using a proteomics approach, we identified signal transducers and activators of transcription-3 (STAT3) as a receptor-binding partner that is mediated by Tyr(677) phosphorylation on FGFR. Binding to activated FGFR was essential for subsequent tyrosine phosphorylation and nuclear translocation of STAT3, along with activation of its downstream target genes. Tyrosine phosphorylation of STAT3 was also dependent on concomitant FGFR-dependent activity of SRC and JAK kinases. Lastly, tyrosine (but not serine) phosphorylation of STAT3 required amplified FGFR protein expression, generated either by enforced overexpression or as associated with gene amplification in cancer cells. Our findings show that amplified FGFR expression engages the STAT3 pathway, and they suggest therapeutic strategies to attack FGFR-overexpressing cancers.
Dudka
Anna A
AA
CRUK Growth Factor Group, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Sweet
Steve M M
SM
Heath
John K
JK
D002460:Cell Line; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism
D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; D014443:Tyrosine; D051497:Receptor, Fibroblast Growth Factor, Type 2; D053613:Janus Kinase 1; D019061:src-Family Kinases
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