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Molecular and Cellular Biology, September 2008, p. 5710-5723, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00186-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CD44 Engagement Promotes Matrix-Derived Survival through the CD44-SRC-Integrin Axis in Lipid Rafts{triangledown} ,{dagger}

Jia-Lin Lee,1 Mei-Jung Wang,1 Putty-Reddy Sudhir,1 and Jeou-Yuan Chen1,2*

Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China,1 Department of Life Sciences, National Yang-Ming University, Taipei 11529, Taiwan, Republic of China2

Received 5 February 2008/ Returned for modification 7 April 2008/ Accepted 7 July 2008

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 β1 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.

* Corresponding author. Mailing address: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2 Academia Road, Taipei 11529, Taiwan, Republic of China. Phone: 886-2-27899046. Fax: 886-2-27858594. E-mail: bmchen{at}ibms.sinica.edu.tw

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2008, p. 5710-5723, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00186-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lee, J.-L., Wang, M.-J., Chen, J.-Y. (2009). Acetylation and activation of STAT3 mediated by nuclear translocation of CD44. JCB 185: 949-957 [Abstract] [Full Text]  


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