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.

MyD88–BLT2-dependent cascade contributes to LPS-induced interleukin-6 production in mouse macrophage

“…We then examined the effects of transient transfection of cells with a MyD88 expression plasmid. 13 Overexpression of MyD88 alone increased the levels of 5-LO and 12-LO as well as the extent of cPLA 2 phosphorylation in Raw 264.7 cells (Figure 3i). In addition, the production of LTB 4 and 12(S)-HETE was significantly increased by forced expression of MyD88 (Figures 3j and k).…”

“…Cells (1 × 10 6 ) were transiently transfected with 2 μg of expression vectors for human MyD88 (pCMV-Flag-MyD88, kindly provided by T Renno) 13 or with the corresponding empty vector (pCMV-Flag), with the use of an MP-100 Microporator (Digital Bio).…”

MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice

“…This was indicated to be through the activation of protein kinase C and expression of tight junction proteins (13). Although a number of experimental models have shown a crucial role for MyD88 in the development of cancer (14,32,37), the biological significance of Mal in epithelial homeostasis and colitis still needs to be fully understood (25). Thus in this study we examined the function of Mal in colon physiopathology by means of preclinical models of colitis and colitis-associated carcinogenesis (CAC).…”

Cell Death Triggered by Yersinia enterocolitica Identifies Processing of the Proinflammatory Signal Adapter MyD88 as a General Event in the Execution of Apoptosis

“…This cleavage could also be a strategy to counteract oncogenesis. MyD88 has been shown to be implicated in carcinogenesis through the induction of inflammation as well as through cell-autonomous mechanisms of cell transformation (47,48). The processing of MyD88 could therefore be a regulatory event protecting against diverse disorders of tissue homeostasis that could arise from malfunctions in apoptosis, such as the development of aberrant inflammatory responses or eventually cancer.…”