Reactome | Ubiquitination of FLT3

Ubiquitination of FLT3

Stable Identifier

R-HSA-9706354

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

plasma membrane

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FLT3 activity is negatively regulated by ubiquitin-mediated internalization (Sargin et al, 2007; Reindl et al, 2009; reviewed in Kazi and Ronnstrand, 2019). Several E3 ubiquitin ligases are implicated in the downregulation of active FLT3 including CBL, SOCS2 and SOCS6 (Sargin et al, 2007, Reindl et al, 2009; Kazi and Ronnstrand, 2013; Kazi et al, 2012).
Ubiquitination of human FLT3 in COS-7 cells is abrogated by the expression of a dominant negative form of CBL, implicating CBL as a major E3 ubiquitin ligase for the FLT3 receptor (Sargin et al, 2007). While direct ubiquitination of FLT3 by SOCS2 and SOCS6 has not been demonstrated, overexpression of these E3 ligases induces FLT3 ubiquitination and internalization in cell lines (Kazi and Ronnstrand, 2012; Kazi and Ronnstrand, 2013; reviewed in Kazi and Ronnstrand, 2019).

Literature References

PubMed ID	Title	Journal	Year
23548639	Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling Kazi, JU, Rönnstrand, L	Mol Oncol	2013
17446348	Flt3-dependent transformation by inactivating c-Cbl mutations in AML Berdel, WE, Grundler, R, Serve, H, Duyster, J, Brandts, C, Tickenbrock, L, Choudhary, C, Koschmieder, S, Dikic, I, Müller-Tidow, C, Schwäble, J, August, B, Thiessen, C, Crosetto, N, Sargin, B, Rensinghoff, M, Bandi, SR, Schmidt, MHH	Blood	2007
22952242	Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3 Flores-Morales, A, Kazi, JU, Sun, J, Zadjali, F, Phung, B, Rönnstrand, L	J Biol Chem	2012
31066629	FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications Kazi, JU, Rönnstrand, L	Physiol. Rev.	2019
19276253	CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes Buske, C, Duyster, J, Reindl, C, Spiekermann, K, Vempati, S, Bohlander, SK, Humphries, KR, Greif, PA, Mellert, G, Argiropoulos, B, Hiddemann, W, Quentmeier, H, Benthaus, T, Petropoulos, K	Clin Cancer Res	2009