Editors' ChoiceCancer

RIGging the Proliferative Response

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Sci. Signal.  18 Feb 2014:
Vol. 7, Issue 313, pp. ec52
DOI: 10.1126/scisignal.2005181

Retinoic acid (RA)–inducible gene I (RIG-I) is well-characterized in its role as a cytosolic pattern recognition receptor that detects viral RNA and stimulates antiviral immunity; however, RIG-I is also implicated in restricting the proliferation of myeloid progenitor cells. Li et al. generated a myeloid cell line (U937 cells) with inducible expression of RIG-I and found that RIG-I led to cellular differentiation, cell-cycle arrest, and cell death in a nonapoptotic manner. The activities of the serine and threonine kinases Akt and its downstream target mammalian target of rapamycin (mTOR) were decreased in U937 cells expressing RIG-I. Conversely, the activity of mTOR was increased in bone marrow (BM)–derived myeloid progenitor cells from RIG-I–deficient mice compared with that in wild-type cells. The enhanced activity of the Akt-mTOR pathway in RIG-I–deficient cells was abolished by an inhibitor of the kinase Src or by expression of a dominant-negative mutant of Src. Coimmunoprecipitation experiments with RIG-I–expressing U937 cells and BM cells showed that RIG-I associated with Src. Src also associated with and tyrosine-phosphorylated Akt in U937 cells, effects that were enhanced when RIG-I was knocked down. Previous studies suggested that Src potentiates the activity of Akt and that enhanced Akt-mTOR signaling initiates acute myeloid leukemia (AML). In a survey of AML patient cells, Li et al. found that 80% of samples showed an inverse correlation between the abundance of RIG-I and the tyrosine phosphorylation of Akt. Coimmunoprecipitation experiments with purified proteins showed that a PxxP motif in RIG-I interacted with the Src homology 3 (SH3) domain of Src and that mutation of this motif prevented RIG-I from blocking the interaction between Src and Akt (Akt also contains a PxxP motif). Stimulation of BM-derived myeloid progenitor cells with the cytokine GM-CSF stimulated their proliferation through the Src-Akt-mTOR pathway, which was enhanced by loss of RIG-I. GM-CSF did not induce proliferation in RIG-I–deficient BM cells reconstituted with the PxxP-mutant RIG-I. Together, these data indicate that RIG-I competes with Akt for binding to Src to restrict the proliferation of myeloid progenitor cells, which suggests that RIG-I may have antileukemia activity.

X.-Y. Li, L.-J. Jiang, L. Chen, M.-L. Ding, H.-Z. Guo, W. Zhang, H.-X. Zhang, X.-D. Ma, X.-Z. Liu, X.-D. Xi, S.-J. Chen, Z. Chen, J. Zhu, RIG-I modulates Src-mediated Akt activation to restrain leukemic stemness. Mol. Cell. 53, 407–419 (2014). [PubMed]