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MR Vol.10 No.1 indexに戻る
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MODERN RHEUMATOLOGY
Vol.10 No.1 |
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Role of the #1 integrin molecule in T-cell
activation and migration |
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| C. Morimoto, H. Kobayashi, R. Nishijima, H. Tanaka,
S. Iwata |
(1)Department of Clinical Immunology and AIDS
Research Center, The Institute of Medical Science, The University
of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
(2) Division of Tumor Immunology, Dana-Farber Cancer Institute and
Department of Medicine, Harvard Medical School, Boston, MA 02115,
USA |
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| Abstract |
| Abstract #1 integrins play crucial roles in a
variety of cell processes such as adhesion, migration, proliferation,
and differentiation of lymphocytes. To understand the molecular mechanisms
of these various biological effects, it is particularly important
to analyze cell signaling through the #1 integrins. Our previous
study showed that PLC-%, pp125FAK (focal adhesion kinase), pp105,
paxillin, p59fyn, p56lck, and ERK1/2 are phosphorylated in their
tyrosine residues upon engagement of #1 integrins. We identified
pp105 as Cas (Crk-associated substrate)-related protein and successfully
cloned its cDNA. pp105 is a Cas homologue predominantly expressed
in the cells of lymphoid lineage, which led us to designate it Cas-L.
Like p130Cas, Cas-L contains a single SH3 domain and multiple SH2-binding
sites (YXXP motif), which are suggested to bind SH2 domains of Crk,
Nck, and SHPTP2. Subsequent studies revealed that pp125FAK binds
Cas-L on its SH3 domain and phosphorylates its tyrosine residues
upon #1 integrin stimulation. Since Cas-L is preferentially expressed
in lymphocytes, it is conceivable that Cas-L plays an important role
in lymphocyte-specific signals. We have shown that Cas-L is involved
in the T-cell receptor (TCR)/CD3 signaling pathway as well as the
#1 integrin signaling pathway. Cas-L is transiently phosphorylated
following CD3 crosslinking and tyrosine-phosphorylated Cas-L binds
to Crk and C3G. Furthermore, a Cas-L mutant (Cas-L(SH3), which lacks
the binding site for FAK, is still tyrosine-phosphorylated upon CD3
crosslinking but not upon #1 integrin crosslinking, suggesting that
FAK is not involved in CD3-dependent Cas-L phosphorylation. Finally,
we have identified a crucial role of Cas-L in #1 integrin-mediated
T-cell co-stimulation. We have found that this co-stimulatory pathway
is impaired in the Jurkat T-cell line, and that the expression level
of Cas-L is reduced in the Jurkat cells compared to peripheral T-cells.
The transfection of Cas-L cDNA into Jurkat cells restored the #1
integrin-mediated co-stimulation, while the transfection of Cas-L(SH3
mutant failed to do so, which contrasts with the case of CD3-mediated
signaling. These results indicate that Cas-L plays a key role, through
the association and phosphorylation by FAK, in #1 integrin-mediated
T-cell co-stimulation. Moreover, tyrosine phosphorylation of Cas-L
is critical for T-cell receptor and #1 integrin-induced T-lymphocyte
migration. Taken together, Cas-L might be the bi-modal docking protein
which assembles the signals through #1 integrins and TCR/CD3, and
which participates in a variety of T-cell functions. |
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| Key words |
Key words &bgr;1-integrins ・ VLA proteins ・ Tyrosine phosphorylation
・ p130Cas (Crk-associated substrate) ・ pp105Cas-L ・ pp125FAK (focal
adhesion kinase) ・ Paxillin
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