Artigo Acesso aberto Revisado por pares

RIG-I Modulates Src-Mediated AKT Activation to Restrain Leukemic Stemness

2014; Elsevier BV; Volume: 53; Issue: 3 Linguagem: Inglês

10.1016/j.molcel.2013.12.008

ISSN

1097-4164

Autores

Xian-Yang Li, Linjia Jiang, Lei Chen, Menglei Ding, He‐Zhou Guo, Wu Zhang, Hongxin Zhang, Xiaodan Ma, Xiang-Zhen Liu, Xiaodong Xi, Sai‐Juan Chen, Chen Zhu, Jiang Zhu,

Tópico(s)

Cytokine Signaling Pathways and Interactions

Resumo

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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