KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages

Blood. 2010 Sep 2;116(9):1559-69. doi: 10.1182/blood-2009-12-257089. Epub 2010 May 26.

Abstract

The matrix metalloproteinase (MMP) MT1-MMP plays pivotal roles in leukocyte physiology such as monocyte diapedesis, dendritic cell migration, and T-cell homing. MT1-MMP is a surface-anchored "master switch" proteinase that cleaves a variety of substrates including extracellular matrix components, matrix receptors, and also other MMPs. However, little is known about the mechanisms enabling intracellular trafficking and exposure of MT1-MMP on the cell surface. We now show that, in primary human macrophages, MT1-MMP-positive vesicles travel bidirectionally along microtubules, in a process regulated by KIF5B and KIF3A/KIF3B kinesins. SiRNA-induced knockdown revealed that transport by KIF5B and KIF3A/KIF3B is crucial for delivery of MT1-MMP to the cell surface and also for surface-associated functions of MT1-MMP, such as shedding of the matrix receptors CD44 and syndecan-1 or degradation of extracellular matrix at podosomes. These data show that kinesin-mediated intracellular transport of MT1-MMP is a pivotal process that allows macrophages to dynamically modify their pericellular environment. These data also identify specific kinesins as potential targets for the early manipulation of MT1-MMP activity in tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Matrix / metabolism*
  • Flow Cytometry
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Kinesin / genetics
  • Kinesin / metabolism*
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Monocytes / cytology
  • Monocytes / metabolism
  • Plasmids
  • Syndecan-1 / metabolism

Substances

  • CD44 protein, human
  • Hyaluronan Receptors
  • KIF3A protein, human
  • KIF3B protein, human
  • KIF5B protein, human
  • SDC1 protein, human
  • Syndecan-1
  • Matrix Metalloproteinase 14
  • Kinesin