CD44 interacts directly with Lck in a zinc-dependent manner

CD44 is a widely expressed cell adhesion molecule with functional similarities to the selectin and integrin adhesion molecules. CD44 has a lectin domain that binds hyaluronan, a component of the extracellular matrix. Interactions between CD44 and hyaluronan promote lymphocyte rolling under flow and...

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Bibliographic Details
Published in:Molecular immunology 2010-06, Vol.47 (10), p.1882-1889
Main Authors: Lefebvre, Dennis C., Lai, Jacqueline C.Y., Maeshima, Nina, Ford, Jennifer L., Wong, Andrea S.L., Cross, Jennifer L., Johnson, Pauline
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
CD44
Cell Adhesion - immunology
Cell Line
Hyaluronan Receptors - metabolism
Immunoprecipitation
Lck
Lymphocyte Activation - immunology
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism
Mice
Polymerase Chain Reaction
Protein interaction
Signal Transduction - immunology
T cell spreading
T-Lymphocytes - metabolism
Zinc
Zinc - metabolism
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Summary:CD44 is a widely expressed cell adhesion molecule with functional similarities to the selectin and integrin adhesion molecules. CD44 has a lectin domain that binds hyaluronan, a component of the extracellular matrix. Interactions between CD44 and hyaluronan promote lymphocyte rolling under flow and cell-cell and cell-matrix adhesion. Attachment of lymphocytes to immobilized CD44 antibodies induces cell adhesion and spreading, which is dependent on Src family kinase activity. Both Lck and Fyn associate with CD44 in T cells. CD4 and CD8 associate with Lck via a zinc-dependent interaction that is inhibited by the divalent metal cation chelator, 1,10-phenanthroline. Here we show that both CD4 and CD44-mediated T cell spreading is abolished in the presence of 1,10-phenanthroline and their association with Lck is significantly reduced. In contrast, the co-immunoprecipitation of Fyn by CD44 was unaffected. The cytoplasmic domain of CD44 was required for divalent cation-dependent association of Lck, but not for its association with Fyn. Mutational analysis of CD44 revealed that cysteine residues were not essential for the interaction nor were the carboxy-terminal 41 amino acids. Progressive deletion of the remaining 31 amino acids of the CD44 cytoplasmic domain revealed the importance of this membrane proximal region for its association with Lck. Using purified recombinant proteins, we demonstrated a direct, zinc-inducible interaction between the cytoplasmic domain of CD44 and Lck but not Fyn. The zinc-inducible interaction required the first 13 amino acids of the cytoplasmic domain of CD44 and the non-catalytic regions of Lck. Taken together, we conclude that CD44 directly associates with Lck in a zinc-inducible manner and this is important for the transmission of CD44-mediated signaling events leading to T cell spreading.
ISSN:0161-5890
1872-9142
DOI:10.1016/j.molimm.2010.03.018