An AMPK-Independent Signaling Pathway Downstream of the LKB1 Tumor Suppressor Controls Snail1 and Metastatic Potential
| Autor: | Robert U. Svensson, Monte M. Winslow, Jonathan M. Goodwin, Reuben J. Shaw, Hua Jane Lou, Benjamin E. Turk |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Epithelial-Mesenchymal Transition Lung Neoplasms AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Biology Article Phosphorylation cascade Mice 03 medical and health sciences 0302 clinical medicine AMP-Activated Protein Kinase Kinases Downregulation and upregulation Cell Line Tumor Animals Humans Neoplasm Invasiveness Phosphorylation skin and connective tissue diseases Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences Protein-Serine-Threonine Kinases Kinase Microfilament Proteins Intracellular Signaling Peptides and Proteins AMPK Cell Biology Cell biology Gene Expression Regulation Neoplastic HEK293 Cells 030220 oncology & carcinogenesis Cancer research Snail Family Transcription Factors Signal transduction Signal Transduction Transcription Factors |
| Zdroj: | Molecular Cell. 55:436-450 |
| ISSN: | 1097-2765 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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