Abstract
Tight regulation of signaling from receptor tyrosine kinases is required for normal cellular functions and uncontrolled signaling can lead to cancer. Fibroblast growth factor receptor 2 (FGFR2) is a receptor tyrosine kinase that induces proliferation and migration. Deregulation of FGFR2 contributes to tumor progression and activating mutations in FGFR2 are found in several types of cancer. Here, we identified a negative feedback loop regulating FGFR2 signaling. FGFR2 stimulates the Ras/MAPK signaling pathway consisting of Ras-Raf-MEK1/2-ERK1/2. Inhibition of this pathway using a MEK1/2 inhibitor increased FGFR2 signaling. The putative ERK1/2 phosphorylation site at serine 780 (S780) in FGFR2 corresponds to serine 777 in FGFR1 which is directly phosphorylated by ERK1/2. Substitution of S780 in FGFR2 to an alanine also increased signaling. Truncated forms of FGFR2 lacking the C-terminal tail, including S780, have been identified in cancer and S780 has been found mutated to leucine in bladder cancer. Substituting S780 in FGFR2 with leucine increased FGFR2 signaling. Importantly, cells expressing these mutated versions of S780 migrated faster than cells expressing wild-type FGFR2. Thus, ERK1/2-mediated phosphorylation of S780 in FGFR2 constitutes a negative feedback loop and inactivation of this feedback loop in cancer cells causes hyperactivation of FGFR2 signaling, which may result in increased invasive properties.
Highlights
Tight regulation of receptor tyrosine kinase signaling is required for specific cellular responses, such as cell growth, differentiation, migration, and apoptosis
Since ERK1/2 signaling can be activated by other receptor tyrosine kinases as well, we investigated if activation of ERK1/2 prior to Fibroblast growth factor receptor 2 (FGFR2) activation would influence the response to FGF1
We identified serine 780 (S780) in FGFR2 to correspond to FGFR1 serine 777 (S777)
Summary
Tight regulation of receptor tyrosine kinase signaling is required for specific cellular responses, such as cell growth, differentiation, migration, and apoptosis. Inadequate regulation of signaling is a common event in cancer development and enhanced receptor signaling promotes tumor growth [1]. The receptor tyrosine kinase, FGFR2 (fibroblast growth factor receptor 2) is a transmembrane, cell-surface localized receptor that belongs to a family of four related receptors [2]. FGFR2 is activated by FGF ligands and induces various downstream signaling molecules. Deregulation of FGFR2 contributes to tumor progression and activating mutations in FGFR2 have been found in different types of cancer, like gastric cancer, breast cancer, and endometrial carcinoma [3,4]. Activating mutations have been found in skeletal disorders, like Apert syndrome and Crouzon syndrome [5]
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