Differential regulation of FGFR3 by PTPN1 and PTPN2.

Abstract

Aberrant expression and activation of FGFR3 is associated with disease states including bone dysplasia and malignancies of bladder, cervix, and bone marrow. MS analysis of protein-phosphotyrosine in multiple myeloma cells revealed a prevalent phosphorylated motif, D/EYYR/K, derived from the kinase domain activation loops of tyrosine kinases including FGFR3 corresponding to a recognition sequence of protein-tyrosine phosphatase PTPN1. Knockdown of PTPN1 or the related enzyme PTPN2 by RNAi resulted in ligand-independent activation of FGFR3. Modulation of FGFR3 activation loop phosphorylation by both PTPN1 and PTPN2 was a function of receptor trafficking and phosphotyrosine phosphatase (PTP) compartmentalization. The FGFR3 activation loop motif DYYKK(650) is altered to DYYKE(650) in the oncogenic variant FGFR3(K650E) , and consequently it is constitutively fully activated and unaffected by activation loop phosphorylation. FGFR3(K650E) was nevertheless remarkably sensitive to negative regulation by PTPN1 and PTPN2. This suggests that in addition to modulating FGFR3 phosphorylation, PTPN1 and PTPN2 constrain the kinase domain by fostering an inactive-state. Loss of this constraint in response to ligand or impaired PTPN1/N2 may initiate FGFR3 activation. These results suggest a model wherein PTP expression levels may define conditions that select for ectopic FGFR3 expression and activation during tumorigenesis.

• Authors: Jonathan R St-Germain, Paul Taylor, Wen Zhang, Zhihua Li, Troy Ketela, Jason Moffat, Benjamin G Neel, Suzanne Trudel, Michael F Moran
• Journal: Proteomics (Proteomics) Vol. 15 Issue 2-3 Pg. 419-33 (Jan 2015) ISSN: 1615-9861 [Electronic] Germany
• PMID: 25311528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Receptor, Fibroblast Growth Factor, Type 3
• PTPN1 protein, human
• PTPN2 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Protein Tyrosine Phosphatase, Non-Receptor Type 2

Topics

• Amino Acid Sequence
• Cell Line, Tumor
• Endocytosis
• Gene Expression Regulation, Neoplastic
• Glycosylation
• Humans
• Molecular Sequence Data
• Multiple Myeloma (genetics, metabolism)
• Phosphorylation
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (analysis, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 2 (analysis, genetics, metabolism)
• RNA Interference
• Receptor, Fibroblast Growth Factor, Type 3 (analysis, genetics, metabolism)