Elucidation of MLK3 Signaling in Tumor Cell Invasion

The majority of cancer-associated deaths are due to metastasis, and understanding mechanisms that initiate this process is essential for targeting aggressive tumors. The process of invasion is a crucial primary step for cancer metastasis, and the mechanisms involved are not fully understood. In this research dissertation, the role for Mixed lineage kinase 3 (MLK3) in the regulation of invasion in melanoma is demonstrated. MLK3 is a mitogen-activated protein kinase kinase kinase (MAP3K) that more recently has been recognized as an important regulator of tumor invasion and metastasis. Using cellular, molecular and biochemical approaches, we have investigated the effects of depleting MLK3 in cutaneous melanoma. We outline a pathway involving BRAF^V600E Hsp90 and Cdc37 that impacts ERK activation, Wnt signaling and regulators of extracellular matrix invasion including the levels and spatial distribution of matrix metalloproteinases. We also investigate MLK3 signaling on uveal melanoma invasion. We demonstrate similarities and differences in the regulation of cutaneous and uveal melanoma invasion. These studies provide critical insights into the role of MLK3 in cutaneous and uveal melanoma cell invasion.