Vimentin Regulates Collagen Remodeling Through Interaction with Myosin 10

Authors:

Ostrowska-Podhorodecka, Z., Ding, I., Abbasi, S., Norouzi, M., Ali, A., Arora, P. D., ... & McCulloch, C. A.

Keywords:

vimentin, myosin-10, MT1-MMP, collagen remodeling

Abstract:

Vimentin (Vim) marks epithelial-mesenchymal transition and increased Vim expression is associated with tumor progression and poor prognosis in colorectal cancer (CRC). Unconventional myosin 10 (Myo10) is an actin-based motor protein whose expression correlates with cancer metastasis, but the interactions of Myo10 with Vim in migrating cells are not defined. Sections of human invasive CRC exhibited prominent colocalization of Myo10 with Vim in cell extensions localized to the subjacent matrix, suggesting an association with local invasion. In mouse fibroblasts, Myo10 co-precipitated with Vim. Surface plasmon resonance showed high affinity binding of Myo10 to Vim (Kd 57 nM). By STED microscopy and FRET analysis, we found that Myo10 interacted with Vim at the termini of cell extensions. Deletion of Vim promoted accumulation of Myo10 at the cell periphery and reduced Myo10 at the tips of extensions. Drug- mediated disassembly of Vim filaments promoted Myo10 retraction from cell extensions into the cell body. FRAP showed that the mobility of Myo10 along cell extensions was impacted by Vim. Myo10 and Vim were required for pericellular collagen degradation by MT1-MMP. Vim deletion reduced the transit of MT1-MMP to the tips of cell extensions and down-regulated collagenolytic activity, which mediated cell invasion of the matrix. Deletion of Vim and Myo10 was associated with reduced collagen fiber alignment and tractional remodeling of the collagen matrix. CRC SW480 cells exhibited similar changes in Myo10 mobility and collagen remodeling after Vim knockdown, similar to mEFs, suggesting that Vim-Myo10 interactions are an important feature of motile cells. Collectively these data indicate that Vim binding to Myo10 promotes collagen remodeling and the generation of cell extensions required for cell migration through soft connective tissues.

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