In this study we characterized for the first time the expression and functionality of the human fibroblast growth factor receptor 1-IIIb variant (FGFR1-IIIb). In situ hybridization demonstrated that FGFR1-IIIb localized in normal pancreatic acinar cells and ductal pancreatic cancer cells. A cDNA encoding the human full-length FGFR1-IIIb was expressed in well-differentiated TAKA–1 pancreatic ductal cells not expressing endogenous FGFR1. FGFR1-IIIb expressing cells synthesized a glycosylated 110 kDa protein capable of inducing proliferation upon incubation with exogenous FGF–1, –2, and –4. Immunoprecipitation experiments revealed that FGF–1 and –2 enhanced tyrosine phosphorylation of FGFR substrate–2 (FRS2) and FGFR1-IIIb and that FRS2 associates with FGFR1-IIIb in these cells. FGF-induced proliferation was associated with activation of the mitogen-activated protein (MAP) kinases p44/42. PD98059 and U0126, inhibitors of the p44/42 MAP kinase pathway, blocked FGF–1-induced p44/42 MAP kinase activation and partially inhibited FGF–1-induced proliferation. FGF–1, –2, and –4 also enhanced p38 MAP and c-Jun (JNK) kinase activation. The p38 MAP kinase inhibitor SB203550 did not alter basal and FGF–1-induced growth. In contrast, the JNK inhibitor SP600125 partially inhibited FGF–1-induced proliferation and abrogated FGF–1 induced JNK activation. The combination of U0126 and SP600125 abolished FGF–1-induced proliferation. Expression of FGFR1-IIIb was also accompanied by enhanced cell adhesion and single cell movement, while basal wound closure was inhibited. Our data demonstrate that human FGFR1-IIIb is a functional transmembrane FGF receptor expressed in the human pancreas. Several FGFs can exert mitogenic effects via FGFR1-IIIb requiring activation of the p44/42 MAP and c-Jun kinase pathways. Additionally, FGFR1-IIIb may be involved in other functions including cell adhesion and cell movement.
Literatur: Kornmann M, Ishiwata T, Matsuda K, Lopez M, Fukahi K, Asano G, Beger HG, Korc M. The IIIc isoform of FGFR-1 is overexpressed in human pancreatic cancer and confers enhanced tumorigenicity to syrian hamster ductal cells. Gastroenterology 2002, 123: 301-313.
Keywords: Fibroblast growth factor receptor, mitogen-activated protein kinases, signal transduction, splice variants
