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J Biol Chem, Vol. 275, Issue 19, 14729-14735, May 12, 2000
From the Department of Immunology, The Scripps Research Institute,
La Jolla, California 92037
The Crk-associated substrate,
p130CAS, has been implicated in the regulation of the
actin cytoskeleton following ligation of cell integrins with the
extracellular matrix. Integrin-mediated cell adhesion involves
p130CAS association with focal adhesion kinase
(p125FAK). Internalization/cell entry of type 2 and type 5 adenoviruses (Ad) is also mediated by
Association of p130CAS with Phosphatidylinositol-3-OH
Kinase Mediates Adenovirus Cell Entry*
v integrins.
However, expression of dominant negative forms of p125FAK
does not alter virus entry, and Ad entry occurs normally in
p125FAK-deficient fibroblasts. We now provide evidence that
Ad internalization, a process which is mediated by v
integrins, also requires p130CAS and
phosphatidylinositol-3-OH kinase (PI 3-kinase). Ad induces p130CAS phosphorylation and inhibition of
p130CAS phosphorylation by tyrphostin and genistein, or
expression of the substrate domain deleted p130CAS blocks
Ad internalization. p130CAS was also found to associate
with the p85 subunit of PI 3-kinase through its proline-rich domain
during virus internalization and expression of p130CAS
containing a deleted proline-rich domain (PRD) inhibited adenovirus cell entry. We showed further that the RPLPSPP motif in the
proline-rich region of p130CAS interacts with the SH3
domain of p85/PI 3-kinase. These studies reveal the molecular basis by
which p130CAS coordinates the signaling pathways involved
in integrin-mediated Ad endocytosis.
*
This work was supported by National Institutes of Health
Grants EY11431 and HL54352. This is manuscript 12486-IMM from The Scripps Research Institute.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Immunology,
The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla,
CA 92037. Tel.: 858-784-8072; Fax: 858-784-8472; E-mail:
gnemerow@scripps.edu.
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