CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain.
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.
Mori
Hidetoshi
H
Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Tomari
Taizo
T
Koshikawa
Naohiko
N
Kajita
Masahiro
M
Itoh
Yoshifumi
Y
Sato
Hiroshi
H
Tojo
Hideaki
H
Yana
Ikuo
I
Seiki
Motoharu
M
D000199:Actins / Q000032:analysis; D000818:Animals; D016466:CHO Cells / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000166:cytology; D006466:Hemopexin / Q000737:chemistry; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D046911:Macromolecular Substances; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology
D000199:Actins; D018960:Hyaluronan Receptors; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; D006466:Hemopexin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases