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Molecular Targets for Therapy

Src inhibitors, PP2 and dasatinib, increase retinoic acid-induced association of Lyn and c-Raf (S259) and enhance MAPK-dependent differentiation of myeloid leukemia cells

Leukemia volume 26, pages 1180–1188 (2012)Cite this article

Abstract

All-trans-retinoic-acid (ATRA)-induced differentiation of human myeloid leukemia cells is characterized by persistent mitogen-activated protein kinase (MAPK) signaling. Fragmentary data suggests Src family kinase (SFK) inhibitors enhance differentiation, and thus have potential therapeutic value. The present study shows that SFK inhibitors PP2 and dasatinib enhance aspects of MAPK signaling and regulate a panel of differentiation markers, including CD11b and p47phox. HL-60 and NB4 myeloid leukemia cells show accelerated ATRA-induced G1/0 arrest/differentiation with inhibitor co-treatment. We also identified components of a Lyn- and c-Raf-containing MAPK signaling complex augmented by the inhibitors. PP2 and dasatinib increased the ATRA-induced expression of Lyn and c-Raf (total and c-RafpS259) and their interaction. The Lyn-associated serine/threonine kinase, casein kinase II (CK2), also complexed with c-Raf and c-RafpS259, and the kinase suppressor of Ras 1 (KSR1) scaffold protein bound c-Raf, Lyn and extracellular signal-regulated kinase (ERK). c-Raf/ERK association was increased by the inhibitors, which is significant as ERK may cause c-Raf C-terminal domain (CTD) phosphorylation in a putative feedback mechanism. Consistent with this, inhibitor treatment caused more CTD phosphorylation. Lyn knockdown decreased c-Raf CTD and S259 phosphorylation. This is the first evidence suggesting SFK inhibitors enhance ATRA-induced differentiation through a possible feedback loop involving KSR1-scaffolded c-Raf and ERK complexed with Lyn and CK2.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) CA033505 (Yen), CA152870 (Yen), 1U54 CA143876 (Shuler), and the New York State Stem Cell Science (NYSTEM) (Yen).

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  1. Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA

    J Congleton, R MacDonald & A Yen

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Correspondence to A Yen.

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Congleton, J., MacDonald, R. & Yen, A. Src inhibitors, PP2 and dasatinib, increase retinoic acid-induced association of Lyn and c-Raf (S259) and enhance MAPK-dependent differentiation of myeloid leukemia cells. Leukemia 26, 1180–1188 (2012). https://doi.org/10.1038/leu.2011.390

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