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Published on: April 26, 2011
RECK isoforms differentially regulate fibroblast migration by modulating tubulin post-translational modifications
Ha Neul Lee1, Oye A Bosompra2, Hilary A Coller3
1Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Abstract:
Cell migration is essential for proper development and the defense against pathogens. Our previous work detailed a pathway of REversion-inducing-Cysteine-rich protein with Kazal motifs (RECK) isoform-mediated invasion in which a shorter RECK protein competes with MMP9 for interaction with the canonical RECK protein on the cell surface. Here we demonstrate that the mechanism through which RECK isoforms affect cell migration is mediated through changes in the levels of post-translational modifications (PTM) of α-tubulin. We show that both the canonical and short RECK isoforms modulate levels of tubulin acetylation and detyrosination. We demonstrate that these changes are sufficient to modulate the rate of fibroblast migration. If these tubulin PTMs are not altered, the effects of the canonical RECK isoform on cell migration are reversed. In defining the molecular pathway linking RECK and tubulin PTMs, we found that MMP9 and integrin activity both act as upstream regulators of tubulin acetylation and detyrosination. Overall, we propose a mechanism in which RECK isoforms on the cell surface have opposing effects on cell migration through MMP9-modulated changes to integrin-extracellular matrix (ECM) interactions that, in turn, affect microtubule PTMs.
Insights
RECK isoforms regulate cell migration by altering α-tubulin post-translational modifications (PTMs). These RECK-mediated changes in tubulin acetylation and detyrosination impact fibroblast migration rates and integrin-extracellular matrix interactions.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cell migration is crucial for development and immunity.
- RECK isoforms influence invasion by interacting with MMP9.
- Previous work identified RECK isoform-mediated invasion pathways.
Purpose of the Study:
- To elucidate the mechanism by which RECK isoforms affect cell migration.
- To investigate the role of α-tubulin post-translational modifications (PTMs) in RECK-mediated cell migration.
- To identify upstream regulators of RECK's effects on tubulin PTMs.
Main Methods:
- Analysis of RECK isoform effects on α-tubulin acetylation and detyrosination.
- Assessment of fibroblast migration rates under varying RECK isoform conditions.
- Investigation of MMP9 and integrin activity in regulating tubulin PTMs.
Main Results:
- Both canonical and short RECK isoforms modulate tubulin acetylation and detyrosination levels.
- Altered tubulin PTMs are sufficient to modulate fibroblast migration rates.
- MMP9 and integrin activity were identified as upstream regulators of tubulin acetylation and detyrosination.
Conclusions:
- RECK isoforms impact cell migration through modulation of α-tubulin PTMs.
- RECK isoforms exert opposing effects on cell migration via MMP9-dependent regulation of integrin-ECM interactions and microtubule PTMs.
- This study defines a molecular pathway linking RECK, MMP9, integrin activity, and tubulin PTMs in regulating cell migration.
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