CD44 engagement promotes matrix-derived survival through the CD44-SRC-integrin axis in lipid rafts.
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.
Lee
Jia-Lin
JL
Institute of Biomedical Sciences, Academia Sinica, 128 Section 2 Academia Road, Taipei 11529, Taiwan, Republic of China.
Wang
Mei-Jung
MJ
Sudhir
Putty-Reddy
PR
Chen
Jeou-Yuan
JY
D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D018960:Hyaluronan Receptors; D019012:Integrin beta1; D020033:Protein Isoforms; D053495:Osteopontin; D019061:src-Family Kinases