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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
CBL mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases.
Exp. Hematol. 41, 271-280 (2013)
In addition to overexpression and the occurrence of activating mutations, receptors can be aberrantly activated by impaired downregulation. Here, it is shown that an oncogenic mutant of the ubiquitin ligase CBL (CBLΔexon8), which is found in AML patients, predominantly cooperates with receptor tyrosine kinase (RTK) class III receptors (PDGFRA, PDGFRB, KIT and FLT3), but not with non-class III RTKs or cytokine receptors, to induce IL-3-independent growth of Ba/F3 cells. In cells co-expressing RTK class III/CBLΔexon8, receptor internalization was delayed and cells were protected from apoptosis after cytokine withdrawal. Ligand-stimulated Ba/F3 cells and AML cell lines co-expressing the CBL deletion mutant and FLT3 showed enhanced AKT phosphorylation. Combined pharmacological inhibition of the PI3K/AKT pathway and FLT3 had an additive effect on cell proliferation. The transforming potential of the CBL mutant was completely abolished by the mutation of the CBL PTB domain and was decreased by the mutation of tyrosines 589 and 591 in the juxtamembrane domain of FLT3. A constitutively active AKT1 mutant (E17K) recapitulated the phenotype induced by the CBL deletion mutant in Ba/F3 cells. This study reveals FLT3-CBL interaction sites and the AKT pathway as critical mediators of transformation by oncogenic CBL mutants.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
ISSN (print) / ISBN
0301-472X
e-ISSN
0301-472X
Zeitschrift
Experimental Hematology
Quellenangaben
Band: 41,
Heft: 3,
Seiten: 271-280
Verlag
Elsevier
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed