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Alternatively spliced variants of FGFR‐1 induce differential signaling to the mitogen activated protein kinase family
Author(s) -
Zhang Pei,
Thompson John Anthony
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a535-a
Subject(s) - fibroblast growth factor receptor , gene isoform , signal transduction , kinase , fibroblast growth factor , biology , microbiology and biotechnology , mapk/erk pathway , cancer research , transfection , receptor , cell culture , biochemistry , genetics , gene
Overexpression of FGF ligands and the alternative spliced FGFR‐1β isoform have been found in malignant pancreatic adenocarcinoma, the fourth leading cause of cancer death in US. In normal adult tissue FGFR‐1 is typically expressed as the α isoform. To examine the biological significance of this feature, FGF receptor–negative endothelial cells (RVEC) were stably transfected with expression vectors encoding either FGFR‐1α or FGFR‐1β human cDNA. In the presence of FGF‐1 treatment, these two isoform transfectants exhibited differential phenotype, migratory behavior, and responses to oxidant stress, ionizing radiation and chemotherapy. These observations have prompted us to examine the intracellular substrates activated by the two receptor isoforms. Immediate early, transient activation of c‐YES and FAK were limited to FGFR‐1β signaling and correlated with altered phenotype, increased migration, and resistance to cytotoxic treatments. Activation of FRS2, SHC and N‐Ras were identified in both isoforms, resulting in sustained activation of ERK1/2 MAPK and mitogenic behavior. Immediate early, transient activation of the stress‐associated MAPKs, p38 and JNK, was restricted to FGFR‐1α signaling in an extracellular calcium‐ and PKC‐dependent manner. Ligand‐activated FGFR‐1α transfectants demonstrated increased sensitivity to cytotoxic treatments. Taken together, these differential signaling pathways may provide mechanistic insight into the onset, progression, and treatment of tumorigenesis.