14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198- FGFR1-transformed hematopoietic cells

Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Blood (Impact Factor: 10.45). 07/2007; 110(1):360-9. DOI: 10.1182/blood-2006-12-065615
Source: PubMed


Human 8p11 stem cell leukemia/lymphoma syndrome usually presents as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-FGFR1 fusion tyrosine kinase that plays a pathogenic role in hematopoietic transformation. We found that ZNF198-FGFR1 activated both the AKT and mitogen activated protein kinase (MAPK) prosurvival signaling pathways, resulting in elevated phosphorylation of the AKT target FOXO3a at T32 and BAD at S112, respectively. These phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis. We used a peptide-based 14-3-3 competitive antagonist, R18, to disrupt 14-3-3-ligand association. Expression of R18 effectively induced apoptosis in hematopoietic Ba/F3 cells transformed by ZNF198-FGFR1 compared with control cells. Moreover, purified recombinant transactivator of transcription (TAT)-conjugated R18 proteins effectively transduced into human leukemia cells and induced significant apoptosis in KG-1a cells expressing FGFR1OP2-FGFR1 fusion tyrosine kinase but not in control HL-60 and Jurkat T cells. Surprisingly, R18 was only able to dissociate FOXO3a, but not BAD as previously proposed, from 14-3-3 binding and induced apoptosis partially through liberation and reactivation of FOXO3a. Our findings suggest that 14-3-3 integrates prosurvival signals in FGFR1 fusion-transformed hematopoietic cells. Disrupting 14-3-3-ligand association may represent an effective therapeutic strategy to treat 8p11 stem cell MPD.

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    • "Yki is not a direct transcriptional factor because it does not possess its own consensus DNA-binding motif but is known as a potent transcriptional co-activator by cooperating with different DNA-binding proteins. Wts directly phosphorylates Yki at Ser 168, thus creating a binding site for 14-3-3 proteins which sequester Yki in the cytoplasm and prevent its nuclear import [44, 45]. In actual fact, the loss of Hippo signaling as well as mutations in 14-3-3 binding site for Yki was shown to produce strong nuclear accumulation, a common feature, coupled with aberrant activity of Yki [47]. "
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    • "The 14-3-3 proteins have raised to a position of integrators of diverse signaling cues that impact cell fate and cancer development [31]. Through regulated interactions with crucial signaling mediators, such as PKC [32] [33], MAPK [34] [35] [36], or AKT [37] [38] [39], 14-3-3 controls diverse cellular responses ranging from signal transduction, cell cycle, metabolism, and apoptosis [31]. Among seven 14-3-3 proteins, 14-3-3ζ, also termed as YWHAZ (tyrosine 3-monooxygenase/tryptophan 5- monooxygenase activation protein, zeta polypeptide), has been shown to play a central role regulating multiple pathways responsible for cancer initiation and progression [40]. "
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