Ectopic Overexpression of MEK5 Suppresses LKB1 Activity: A Novel Mechanism of Regulating LKB1 Open Access

Huang, Henry (2015)

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The inactivation of LKB1 kinase has been shown to play a key role in lung cancer cell metastasis. The LKB1 gene is frequently inactivated at the DNA level in non-small cell lung cancer by somatic mutation. LKB1 can also be inactivated at the protein level by a B-RAF V600E mutation through MEK1/2 and ERK1/2 signaling in melanoma cells. Here we introduce a third possible mechanism of LKB1 inactivation at the protein level, through the MEK5 pathway. The overexpression of MEK5 was found to attenuate LKB1-mediated AMPK phosphorylation in H1299 cells under glucose-free conditions. MEK5 was found to bind to LKB1 in a GST pull-down assay, and both kinase-dead and phosphomimetic MEK5 mutants were found to have increased binding affinity for LKB1. BIX02188, a MEK5 kinase inhibitor, was found to disrupt the interaction between LKB1 and MEK5. Surprisingly, neither of the MEK5 mutants was capable of suppressing LKB1 kinase activity, suggesting that the increase in binding affinity of MEK5 to LKB1 does not play a role in suppressing LKB1 kinase activity. Depletion of MEK5 isoform C promoted the half-life of LKB1, suggesting that MEK5 may play a role in promoting the degradation of LKB1. LKB1 is known to be a tumor suppressor in breast cancer but the mechanism of LKB1 inactivation in that tumor type is currently unknown. Our data suggest that the recently identified MEK5 amplification in breast xenografts may be responsible for LKB1 inactivation in breast tumors.

Table of Contents

Introduction 1

Hypothesis 4

Research Aims 4

Methods and Materials 5

Results 9

Discussion 15

Table and Figures 21

Acknowledgements 34

References 35

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