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Cancer metastasis causes &gt;90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.

The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis