Differential regulation of FGFR3 by PTPN1 and PTPN2. Issue 2 (17th December 2014)

• Record Type: Journal Article
• Authors: St‐Germain, Jonathan R.; Taylor, Paul; Zhang, Wen; Li, Zhihua; Ketela, Troy; Moffat, Jason; Neel, Benjamin G.; Trudel, Suzanne; Moran, Michael F.; Pandey, Akhilesh; Moran, Michael F.
• Is Part Of: Proteomics. Volume 15:Issue 2/3(2015)
• Page Start: 419
• Page End: 433
• Publication Date: 2014-12-17
• Subjects: Proteins -- Separation -- Periodicals; Bioinformatics -- Periodicals; Proteomics -- Periodicals; Genomes -- Periodicals; Molecular genetics -- Periodicals; 572.605
• DOI: 10.1002/pmic.201400259
• Languages: English
• ISSNs: 1615-9853

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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<sup>650</sup> is altered to DYYKE<sup>650</sup> in the oncogenic variant FGFR3<sup>K650E</sup>, and consequently it is constitutively fully activated and unaffected by activation loop phosphorylation. FGFR3<sup>K650E</sup> 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.</p> </abstract>