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Membrane-type 1 matrix metalloproteinase (MT1- MMP) localizes at the front of migrating cells and degrades the extracellular matrix barrier during cancer invasion. However, it is poorly understood how the polarized distribution of MT1-MMP at the migration front is regulated. Here, we demonstrate that MT1-MMP forms a complex with CD44H via the hemopexin-like (PEX) domain. A mutant MT1-MMP lacking the PEX domain failed to bind CD44H and did not localize at the lamellipodia. The cytoplasmic tail of CD44H, which comprises interfaces that associate with the actin cytoskeleton, was important for its localization at lamellipodia. Overexpression of a CD44H mutant lacking the cytoplasmic tail also prevented MT1-MMP from localizing at the lamellipodia. Modulation of F-actin with cytochalasin D revealed that both CD44H and MT1-MMP co-localize closely with the actin cytoskeleton, dependent on the cytoplasmic tail of CD44H. Thus, CD44H appears to act as a linker that connects MT1-MMP to the actin cytoskeleton and to play a role in directing MT1-MMP to the migration front. The PEX domain of MT1-MMP was indispensable in promoting cell migration and CD44H shedding.

Original publication

DOI

10.1093/emboj/cdf411

Type

Journal article

Journal

EMBO J

Publication Date

01/08/2002

Volume

21

Pages

3949 - 3959

Keywords

Actins, Animals, Antigens, CD44, CHO Cells, Cell Membrane, Cell Movement, Cercopithecus aethiops, Cricetinae, Cricetulus, Cytoskeleton, Fibroblasts, Hemopexin, Humans, Macromolecular Substances, Matrix Metalloproteinases, Membrane-Associated, Metalloendopeptidases, Protein Interaction Mapping, Protein Structure, Tertiary, Protein Transport, Pseudopodia, Recombinant Fusion Proteins, Sequence Deletion, Structure-Activity Relationship, Transfection, Tumor Cells, Cultured