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 phosphotyrosine phosphatases 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 PTP compartmentalization. The FGFR3 activation loop motif DYYKK650 is altered to DYYKE650 in the oncogenic variant FGFR3K650E, and consequently it is constitutively fully activated and unaffected by activation loop phosphorylation. FGFR3K650E 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.

Deoxyribonuclease 1-like 3 Inhibits Hepatocellular Carcinoma Progression by Inducing Apoptosis and Reprogramming Glucose Metabolism

“…PTPN2 is a known critical negative modulator of JAK/STAT signaling, and works to dephosphorylate receptor protein tyrosine kinases such as PDGFR, CSF1R, EGFR and INSR [16]. PTPN2 also dephosphorylates non-receptor protein tyrosine kinases such as STAT1, STAT3, and STAT6, Src family kinases as well as JAK1, JAK2 and JAK3 [17]. Then we investigated the relationship between DNASE1L3 and PTPN2 in HCC progression.…”

A Place for Precision Medicine in Bladder Cancer: Targeting the Fgfrs

“…These include the Sprouty proteins (SPRY 1-4) that are upregulated in response to FGFR signaling through MAPK and provide feedback inhibition by binding to adapter proteins GRB2 and SOS1 [81]. Regulation of Sprouty turnover by CBL may also play a role [82], as may changes in expression of key regulatory proteins such as FRS2 or phosphatases that act on FGFR3 [83,84]. Other potential negative regulatory proteins include SEF and DUSP proteins [85].…”

The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1

“…A key family of TCPTP (hereafter referring to the TC45 isoform throughout the manuscript; Fig. 1a ) substrates are receptor tyrosine kinases (RTKs), including the Insulin receptor (IR) 7 , 8 , Epidermal growth factor receptor (EGFR) 9 , Platelet-derived growth factor receptor (PDGFR) 10 , Vascular endothelial growth factor receptor (VEGFR) 11 , Fibroblast growth factor receptor (FGFR3) 12 , Colony-stimulating factor-1 receptor (CSF1R) 13 , and Hepatocyte growth factor receptor (C-Met) 14 . TCPTP dephosphorylates the RTK activation loop phosphorylation sites, thereby directly controlling RTK activity.…”