Protein Tyrosine Phosphatase Receptor Type G (PTPRG) Controls Fibroblast Growth Factor Receptor (FGFR) 1 Activity and Influences Sensitivity to FGFR Kinase Inhibitors

Abstract

Recently, FGFR1 was found to be overexpressed in osteosarcoma and represents an important target for precision medicine. However, because targeted cancer therapy based on FGFR inhibitors has so far been less efficient than expected, a detailed understanding of the target is important. We have here applied proximity-dependent biotin labeling combined with label-free quantitative mass spectrometry to identify determinants of FGFR1 activity in an osteosarcoma cell line. Many known FGFR interactors were identified (e.g. FRS2, PLCG1, RSK2, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization

“…Although the mechanism of FGFR1 activation and signaling is well studied, the knowledge about trafficking of FGFR1 is far from complete. Recent proteomic studies revealed several proteins that may modulate intracellular transport of FGFR1, however, the exact role of these factors in FGFR1 trafficking awaits further studies [31,42]. FGFR1 is subjected to the constitutive low‐rate internalization from the plasma membrane.…”

“…We have recently uncoupled FGFR1 dimerization from the receptor activation and have demonstrated that dimerization of FGFR1, but not receptor autophosphorylation, triggers CME of FGFR1 [5,6]. A number of proteins involved in CME of FGFR1 in response to FGF binding were identified,however, the exact role of a number of these factors in the receptor internalization is still largely mysterious [31,40–44]. Besides CME, clathrin‐independent endocytosis (CIE) may participate in FGFR1 internalization [34,45,46].…”

The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases

“…A homogenous clone with moderate FGFR4-GFP expression was chosen for further studies. U2OS cells stably expressing FGFR1-GFP and FGFR1-BirA-HA have been described (76). For generation of truncated SHIP2 variants, the C-terminal (17,45,81).…”

Differential regulation of fibroblast growth factor receptor 1 trafficking and function by extracellular galectins

“…The cellular trafficking and function of FGFR1 depends on the receptor interaction with specific partner proteins. Up to date a few attempts to identify proteins that bind FGFR1 were reported [42,43]. Here, we sought to identify novel proteins that adjust FGFR1 function and cellular distribution.…”

“…We used model U2OS-SBP-R1 cells producing streptavidin-binding peptide (SBP)-tagged FGFR1 (SBP-FGFR1) and U2OS-R1 cells stably expressing non-tagged FGFR1 as a control [43]. At steady state conditions FGFR1 is localized to the plasma membrane [44][45][46].…”