Abstract
MLK3 kinase activates multiple mitogen-activated protein kinases and plays a critical role in cancer cell migration and invasion. In the tumor microenvironment, prometastatic factors drive breast cancer invasion and metastasis, but their associated signaling pathways are not well-known. Here, we provide evidence that MLK3 is required for chemokine (CXCL12)-induced invasion of basal breast cancer cells. We found that MLK3 induced robust phosphorylation of the focal adhesion scaffold paxillin on Ser 178 and Tyr 118, which was blocked by silencing or inhibition of MLK3-JNK. Silencing or inhibition of MLK3, inhibition of JNK, or expression of paxillin S178A all led to enhanced Rho activity, indicating that the MLK3-JNK-paxillin axis limits Rho activity to promote focal adhesion turnover and migration. Consistent with this, MLK3 silencing increased focal adhesions and stress fibers in breast cancer cells. MLK3 silencing also decreased the formation of breast cancer lung metastases in vivo, and breast cancer cells derived from mouse lung metastases showed enhanced Ser 178 paxillin phosphorylation. Taken together, our findings suggest that the MLK3-JNK-paxillin signaling axis may represent a potential therapeutic target and/or prognostic marker in breast cancer metastasis.
Highlights
Recent decreases in breast cancer mortality are primarily because of improved diagnosis and treatment
CXCL12induced migration was completely blocked in MDA-MB-231 cells stably expressing shMlk3 or treated with CEP-1347, a selective MLK inhibitor (Fig. 1A)
We report, for the first time, that in response to CXCL12 and Hepatocyte growth factor/scatter factor (HGF), MLK3 signals to JNK to control phosphorylation of paxillin on both Ser 178 and Tyr 118 (Figs. 2–4), phosphorylation events that are essential in cell migration [24, 35]
Summary
Recent decreases in breast cancer mortality are primarily because of improved diagnosis and treatment. Approximately 40,000 deaths annually in the United States are due to breast cancer [1], primarily from metastasis to distant organs. Metastasis is a multistep process requiring tumor cell migration, intravasation, survival in circulation, extravasation, and colonization to a secondary site. Interrupting the metastatic process is key to reducing breast cancer mortality. Chemokines and growth factors drive breast cancer migration, invasion, and metastasis. The chemokine, CXCL12/SDF1a, binds its G-protein–coupled receptor, CXCR4, to promote cytoskeletal remodeling and migration in human breast cancer cells [2], and CXCL12-CXCR4 signaling is critical for breast cancer metastasis in mouse xenograft models [2, 3]. Hepatocyte growth factor/scatter factor (HGF), through binding to its receptor, Authors' Affiliations: Departments of 1Biochemistry and Molecular Biology, 2Physiology, 3Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan
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