Journal
MOLECULAR CELL
Volume 53, Issue 3, Pages 407-419Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.12.008
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Funding
- National Scientific Foundation of China [81090412, 81070391, 81270628]
- Chinese National Key Basic Research Project [2007CB947801, 2013CB966803]
- Shanghai Municipal Committee of Science and Technology [06dj14002, 09XD1403000]
- E-Institute of Shanghai Municipal Education Commission [E03003]
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Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.
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