Dual function of MyD88 in RAS signaling and inflammation, leading to mouse and human cell transformation
Isabelle Coste, … , Serge Lebecque, Toufic Renno
Isabelle Coste, … , Serge Lebecque, Toufic Renno
Published September 13, 2010
Citation Information: J Clin Invest. 2010;120(10):3663-3667. https://doi.org/10.1172/JCI42771.
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Brief Report Oncology

Dual function of MyD88 in RAS signaling and inflammation, leading to mouse and human cell transformation

Abstract

Accumulating evidence points to inflammation as a promoter of carcinogenesis. MyD88 is an adaptor molecule in TLR and IL-1R signaling that was recently implicated in tumorigenesis through proinflammatory mechanisms. Here we have shown that MyD88 is also required in a cell-autonomous fashion for RAS-mediated carcinogenesis in mice in vivo and for MAPK activation and transformation in vitro. Mechanistically, MyD88 bound to the key MAPK, Erk, and prevented its inactivation by its phosphatase, MKP3, thereby amplifying the activation of the canonical RAS pathway. The relevance of this mechanism to human neoplasia was suggested by the finding that MyD88 was overexpressed and interacted with activated Erk in primary human cancer tissues. Collectively, these results show that in addition to its role in inflammation, MyD88 plays what we believe to be a crucial direct role in RAS signaling, cell-cycle control, and cell transformation.

Authors

Isabelle Coste, Katy Le Corf, Alain Kfoury, Isabelle Hmitou, Sabine Druillennec, Pierre Hainaut, Alain Eychene, Serge Lebecque, Toufic Renno

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Figure 3

MyD88 induces Erk-dependent transformation of fibroblasts in vitro and interacts with p-Erk in primary human cancers.

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MyD88 induces Erk-dependent transformation of fibroblasts in vitro and i...
(A) NIH 3T3 fibroblasts were transfected with Myc and either empty vector, MyD88 WT, MyD88 R/M, or MyD88-E52A. Antibiotic-selected MyD88 WT– and MyD88-E52A–, but not MyD88 R/M–transfected cells started showing signs of microscopic morphological transformation after 10 days of culture and (B) focus formation 3 weeks after culture. (C–F) MyD88 and p-Erk interaction in primary lung tumor tissue revealed by proximity ligation assay (red dots). Paraffin sections were stained with antibodies to MyD88 and p-Erk followed by the appropriate DNA-linked secondary antibodies according to the Duolink protocol. Shown are normal peritumoral epithelium (within the white outline) (C) and glandular tumor structures (D–F) from the same section.