biostudies-literatureBalinda HUNCI NIH HHS113106https://www.ebi.ac.uk/biostudies/studies/S-EPMC9086996biostudies-literatureUnknown415(1)Invasive melanoma is an aggressive form of skin cancer with high incidence of mortality. The process of tumor invasion is a crucial primary step in the metastatic cascade, yet the mechanisms involved are still under investigation. Here we document a critical role for MLK3 (MAP3K11) in the regulation of melanoma cell invasion. We report the unexpected finding that cellular loss of MLK3 in melanoma cells promotes cell invasion. Cellular depletion of MLK3 expression results in the hyperactivation of ERK, which is linked to the formation of a BRAF/Hsp90/Cdc37 protein complex. ERK hyperactivation leads to enhanced phosphorylation and inactivation of GSK3β and the stabilization of c-Jun and JNK activity. Blocking of ERK and JNK signaling as well as Hsp90 activity downstream of MLK3-silencing sigExperimental cell researchMechanisms underlying melanoma invasion as a consequence of MLK3 loss.PMC9086996R01 CA115316Balinda HUSedgwick AD'Souza-Schorey CfalseMechanisms underlying melanoma invasion as a consequence of MLK3 loss.Invasive melanoma is an aggressive form of skin cancer with high incidence of mortality. The process of tumor invasion is a crucial primary step in the metastatic cascade, yet the mechanisms involved are still under investigation. Here we document a critical role for MLK3 (MAP3K11) in the regulation of melanoma cell invasion. We report the unexpected finding that cellular loss of MLK3 in melanoma cells promotes cell invasion. Cellular depletion of MLK3 expression results in the hyperactivation of ERK, which is linked to the formation of a BRAF/Hsp90/Cdc37 protein complex. ERK hyperactivation leads to enhanced phosphorylation and inactivation of GSK3β and the stabilization of c-Jun and JNK activity. Blocking of ERK and JNK signaling as well as Hsp90 activity downstream of MLK3-silencing sig2022-01-01T00:00:00Z2022 Jun2025-04-26T22:53:30.195Z2025-04-06T17:23:49.272ZS-EPMC90869963530740910.1016/j.yexcr.2022.113106