CD44 engagement promotes matrix-derived survival through the CD44-SRC-integrin axis in lipid rafts

Mol Cell Biol. 2008 Sep;28(18):5710-23. doi: 10.1128/MCB.00186-08. Epub 2008 Jul 21.


CD44 is present in detergent-resistant, cholesterol-rich microdomains, called lipid rafts, in many types of cells. However, the functional significance of CD44 in lipid rafts is still unknown. We have previously demonstrated that osteopontin-mediated engagement of CD44 spliced variant isoforms promotes an extracellular matrix-derived survival signal through integrin activation. By using a series of CD44 mutants and pharmacological inhibitors selectively targeted to various cellular pathways, we show in this study that engagement of CD44 induces lipid raft coalescence to facilitate a CD44-Src-integrin signaling axis in lipid rafts, leading to increased matrix-derived survival. Palmitoylation of the membrane-proximal cysteine residues and carboxyl-terminal linkage to the actin cytoskeleton both contribute to raft targeting of CD44. The enrichment of integrin beta1 in lipid rafts is tightly coupled to CD44 ligation-elicited lipid raft reorganization and associated with temporally delayed endocytosis. Through the interaction with the CD44 carboxyl-terminal ankyrin domain, Src is cotranslocated to lipid rafts, where it induces integrin activation via an inside-out mechanism. Collectively, this study demonstrates an important role of the dynamic raft reorganization induced by CD44 clustering in eliciting the matrix-derived survival signal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Apoptosis / physiology
  • Cell Adhesion / physiology
  • Cell Line
  • Cell Survival*
  • Cytoskeleton / metabolism
  • Extracellular Matrix / metabolism*
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Membrane Microdomains / chemistry
  • Membrane Microdomains / metabolism*
  • Osteopontin / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Signal Transduction / physiology*
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • Actins
  • Hyaluronan Receptors
  • Integrin beta1
  • Protein Isoforms
  • Osteopontin
  • src-Family Kinases