PTPRJ dephosphorylates active FLT3

Stable Identifier
R-HSA-9698408
Type
Reaction [transition]
Species
Homo sapiens
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The protein tyrosine phosphatase PTPRJ (also known as DEP1) dephosphorylates active FLT3 on juxtamembrane tyrosine residues Y589, Y591 and Y599 and Y955 and on kinase domain tyrosine residues Y842 (not shown) and Y955. Dephosphorylation negative regulates FLT3-dependent signaling, particularly through the ERK and PLCgamma pathways, with moderate effects on STAT signaling and minor effects on signaling through AKT (Arora et al, 2011). Dephosphorylation is effected through a direct interaction between the phosphatase and the active receptor. Depletion of PTPRJ by shRNA caused proliferation and colony formation of the mouse myeloid cell line 32D in the presence of ligand but did not promote myeloid disease development (Arora et al, 2011). FLT3 ITD mutants also directly interact with PTPRJ, but autophosphorylation of the mutant receptors is not affected by PTPRJ depletion (Arora et al, 2011). FLT3 ITD insensitivity to PTPTJ-mediated dephosphorylation is the result of increased reactive oxygen (ROS) levels in FLT3 mutants cells, which inactivate the catalytic activity of PTPRJ (Sallmyr et al, 2008; Reddy et al, 2011; Godfrey et al, 2012; Kresinsky et al, 2015; Jayavelu et al, 2016; reviewed in Jayavelu et al, 2016).

Literature References
PubMed ID Title Journal Year
22438257 Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ

Godfrey, R, Arora, D, Bauer, R, Stopp, S, Müller, JP, Heinrich, T, Böhmer, SA, Dagnell, M, Schnetzke, U, Scholl, S, Östman, A, Böhmer, FD

Blood 2012
27666490 NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

Jayavelu, AK, Moloney, JN, Böhmer, FD, Cotter, TG

Exp. Hematol. 2016
21072051 NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases

Reddy, MM, Fernandes, MS, Salgia, R, Levine, RL, Griffin, JD, Sattler, M

Leukemia 2011
26308771 NOX4-driven ROS formation mediates PTP inactivation and cell transformation in FLT3ITD-positive AML cells

Jayavelu, AK, Müller, JP, Bauer, R, Böhmer, SA, Lässig, J, Cerny-Reiterer, S, Sperr, WR, Valent, P, Maurer, B, Moriggl, R, Schröder, K, Shah, AM, Fischer, M, Scholl, S, Barth, J, Oellerich, T, Berg, T, Serve, H, Frey, S, Fischer, T, Heidel, FH, Böhmer, FD

Leukemia 2016
18192505 Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML

Sallmyr, A, Fan, J, Datta, K, Kim, KT, Grosu, D, Shapiro, P, Small, D, Rassool, F

Blood 2008
21262971 Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling

Arora, D, Stopp, S, Böhmer, SA, Schons, J, Godfrey, R, Masson, K, Razumovskaya, E, Rönnstrand, L, Tänzer, S, Bauer, R, Böhmer, FD, Müller, JP

J. Biol. Chem. 2011
29880609 Loss of DEP-1 (Ptprj) promotes myeloproliferative disease in FLT3-ITD acute myeloid leukemia

Kresinsky, A, Bauer, R, Schnöder, TM, Berg, T, Meyer, D, Ast, V, König, R, Serve, H, Heidel, FH, Böhmer, FD, Müller, JP

Haematologica 2018
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Catalyst Activity
Title
protein tyrosine phosphatase activity of PTPRJ [plasma membrane]
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