FLT3 ITD mutants phosphorylate STAT5

Stable Identifier
R-HSA-9698005
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane
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FLT3 ITD mutants phosphorylate STAT5
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STAT5 is phosphorylated downstream of FLT3 ITD mutants (Hayakawa et al, 2000; Mizuki et al, 2000; Spiekermann et al, 2003, Rocnik et al, 2006). Recombinant FLT3 ITD is able to directly phosphorylate STAT5 in vitro, but phosphorylation may also be mediated by SRC family kinases in vivo (Choudhary et al, 2007; Leischner et al, 2012; Voisset et al, 2010; reviewed in Kazi and Ronnstrand, 2019 a, b). FLT3-dependent STAT5 activation contributes to the expression of a number of genes involved in proliferation and transformation (Mizuki et al 2003; Takahashi et al, 2004; Kim et al, 2005; Nabinger et al, 2013; Bertoli et al, 2015; reviewed in Kazi and Ronnstrand, 2019 a).

Literature References
PubMed ID Title Journal Year
20111072 FES kinases are required for oncogenic FLT3 signaling

Voisset, E, De Sepulveda, P, Chaix, A, Hanssens, K, Georges, C, Prébet, T, Lopez, S, Dubreuil, P

Leukemia 2010
16627759 Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD

Gilliland, DG, Rocnik, JL, Schenkein, DP, Yu, JC, Giese, N, Okabe, R, Lee, BH

Blood 2006
30552988 The role of SRC family kinases in FLT3 signaling

Kazi, JU, Rönnstrand, L

Int. J. Biochem. Cell Biol. 2019
10698507 Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines

Hayakawa, F, Saito, H, Towatari, M, Tanimoto, M, Naoe, T, Kitamura, T, Kiyoi, H

Oncogene 2000
15498859 Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival

Levis, M, Ahn, JY, Small, D, Lilly, M, Kim, KT, Meltzer, P, Baird, K

Blood 2005
12796379 Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells

Schwab, R, Spiekermann, K, Schmieja, K, Bagrintseva, K, Hiddemann, W

Clin. Cancer Res. 2003
11090077 Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways

Büchner, T, Kratz-Albers, K, Serve, H, Matsumura, I, Müller, C, Serve, S, Steur, C, Kanakura, Y, Berdel, WE, Schmidt, R, Halfter, H, Fenski, R, Grüning, W, Kienast, J, Mizuki, M

Blood 2000
26515730 CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia

Delabesse, E, Manenti, S, Demur, C, Galcera, MO, Didier, C, Saland, E, Mansat-De Mas, V, Sarry, JE, Boutzen, H, Hospital, MA, David, L, Fernandez-Vidal, A, Tamburini, J, Bertoli, S, Dozier, C, Yuan, L, Larrue, C, Vergez, F, Récher, C

Oncotarget 2015
15003515 Flt3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5

Licht, JD, Harigae, H, Takahashi, S, Kaku, M, Sasaki, T

Biochem. Biophys. Res. Commun. 2004
23103841 The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo

Boswell, HS, Ramdas, B, Feng, GS, Zeng, L, Kapur, R, He, Y, Liu, Z, Zhang, X, Sandusky, GE, Zhang, ZY, Fukuda, S, Li, XJ, Nabinger, SC, Yu, M, Richine, B, Chan, RJ, Goenka, S, Bowling, JD

Leukemia 2013
22411868 SRC is a signaling mediator in FLT3-ITD- but not in FLT3-TKD-positive AML

Grundler, R, Leischner, H, Duyster, J, Götze, K, Spiekermann, K, Razumovskaya, E, Peschel, C, Bohlander, S, Rönnstrand, L, Albers, C

Blood 2012
31066629 FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi, JU, Rönnstrand, L

Physiol. Rev. 2019
17356133 Activation mechanisms of STAT5 by oncogenic Flt3-ITD

Berdel, WE, Serve, H, Sargin, B, Ueker, A, Böhmer, FD, Brandts, C, Tickenbrock, L, Choudhary, C, Müller-Tidow, C, Schwäble, J

Blood 2007
12468433 Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations

Berdel, WE, Serve, H, Kanakura, Y, Choudhary, C, Müller-Tidow, C, Schwäble, J, Agrawal, S, Matsumura, I, Steffen, B, Sargin, B, Böhmer, FD, Mizuki, M, Steur, C

Blood 2003
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein tyrosine kinase activity of p-6Y FLT3 ITD mutant dimers:GRB2:p-Y GAB2:PTPN11:STAT5 [plasma membrane]

Physical Entity
p-6Y FLT3 ITD mutant dimers:GRB2:p-Y GAB2:PTPN11:STAT5 [plasma membrane] (Homo sapiens)
Activity
protein tyrosine kinase activity (GO:0004713)
Normal reaction
Activator phosphorylates STAT5 (Homo sapiens)
Functional status

Gain of function of p-6Y FLT3 ITD mutant dimers:GRB2:p-Y GAB2:PTPN11:STAT5 [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2020-11-06)
Reviewed
Kazi, JU  (2020-11-06)
Created
Rothfels, K  (2020-08-21)
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