An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential

Jonathan M Goodwin; Robert U Svensson; Hua Jane Lou; Monte M Winslow; Benjamin E Turk; Reuben J Shaw

doi:10.1016/j.molcel.2014.06.021

An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential

Mol Cell. 2014 Aug 7;55(3):436-50. doi: 10.1016/j.molcel.2014.06.021. Epub 2014 Jul 17.

Authors

Jonathan M Goodwin¹, Robert U Svensson¹, Hua Jane Lou², Monte M Winslow³, Benjamin E Turk², Reuben J Shaw⁴

Affiliations

¹ Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
² Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
³ Department of Genetics and Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
⁴ Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: shaw@salk.edu.

Abstract

The serine/threonine kinase LKB1 is a tumor suppressor whose loss is associated with increased metastatic potential. In an effort to define biochemical signatures of metastasis associated with LKB1 loss, we discovered that the epithelial-to-mesenchymal transition transcription factor Snail1 was uniquely upregulated upon LKB1 deficiency across cell types. The ability of LKB1 to suppress Snail1 levels was independent of AMPK but required the related kinases MARK1 and MARK4. In a screen for substrates of these kinases involved in Snail regulation, we identified the scaffolding protein DIXDC1. Similar to loss of LKB1, DIXDC1 depletion results in upregulation of Snail1 in a FAK-dependent manner, leading to increased cell invasion. MARK1 phosphorylation of DIXDC1 is required for its localization to focal adhesions and ability to suppress metastasis in mice. DIXDC1 is frequently downregulated in human cancers, which correlates with poor survival. This study defines an AMPK-independent phosphorylation cascade essential for LKB1-dependent control of metastatic behavior.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases / metabolism*
Animals
Cell Line, Tumor
Epithelial-Mesenchymal Transition / genetics
Epithelial-Mesenchymal Transition / physiology
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / chemistry*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Lung Neoplasms
Mice
Microfilament Proteins / chemistry*
Microfilament Proteins / genetics
Microfilament Proteins / metabolism*
Neoplasm Invasiveness / genetics*
Neoplasm Invasiveness / pathology
Phosphorylation
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction
Snail Family Transcription Factors
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

DIXDC1 protein, human
Intracellular Signaling Peptides and Proteins
Microfilament Proteins
SNAI1 protein, human
Snai1 protein, mouse
Snail Family Transcription Factors
Transcription Factors
MARK1 protein, human
MARK4 protein, human
Protein Serine-Threonine Kinases
STK11 protein, human
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding