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J. Biol. Chem., Vol. 276, Issue 1, 729-737, January 5, 2001
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From the CD43, one of the most abundant glycoproteins on
the T cell surface, has been implicated in selection and maturation of
thymocytes and migration, adhesion, and activation of mature T cells.
The adapter molecule Cbl has been shown to be a negative regulator of
Ras. Furthermore, it may also regulate intracellular signaling through
the formation of several multi-molecular complexes. Here we
investigated the role of Cbl in the CD43-mediated signaling pathway in
human T cells. Unlike T cell receptor signaling, the interaction
of the adapter protein Cbl with Vav and phosphatidylinositol 3-kinase,
resulting from CD43-specific signals, is independent of Cbl tyrosine
phosphorylation, suggesting an alternative mechanism of interaction.
CD43 signals induced a Cbl serine phosphorylation-dependent interaction with the
Regulation of Cbl Molecular Interactions by the Co-receptor
Molecule CD43 in Human T Cells*
,
,
,
,
**
Instituto de
Biotecnología/Universidad Nacional Autónoma de
México, Apartado Postal 510-3, Cuernavaca, MOR 62250, Mexico, the § Dana Farber Cancer Institute, Boston,
Massachusetts 02115, and the ¶ La Jolla Institute for Allergy and
Immunology, La Jolla, California 92121
-isoform of 14-3-3. protein. Protein
kinase C-mediated Cbl serine phosphorylation was required for this
interaction, because the PKC inhibitor RO-31-8220 prevented it, as well
as 14-3-3 dimerization. Moreover, mutation of Cbl serine residues 619, 623, 639, and 642 abolished the interaction between Cbl and 14-3-3. Overexpression of Cbl in Jurkat cells inhibited the
CD43-dependent activation of the mitogen-activated protein
kinase (MAPK) pathway and AP-1 transcriptional activity, confirming
nevertheless a negative role for Cbl in T cell signaling. However,
under normal conditions, PKC activation resulting from CD43 engagement
was required to activate the MAPK pathway, suggesting that
phosphorylation of Cbl on serine residues by PKC and its association
with 14-3-3 molecules may play a role in preventing the Cbl inhibitory
effect on the Ras-MAPK pathway. These data suggest that by inducing its phosphorylation on serine residues, CD43-mediated signals may regulate
the molecular associations and functions of the Cbl adapter protein.
*
This work was supported by Grant IN217498 from
Dirección General de Apoyo al Personal
Académico/Universidad Nacional Autónoma de
México and Grant 25307-M from Consejo Nacional de Ciencia y Tecnologia, México.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.
Present address: Kyoto University Faculty of Medicine.
Sakyo-ku, Kyoto 606-8315, Japan.
**
To whom correspondence should be addressed: Instituto de
Biotecnología/UNAM, APDO Postal 510-3, Cuernavaca, MOR 62250, Mexico. Tel.: 52-73-291606; Fax: 52-73-172388; E-mail:
yvonne@ibt.unam.mx.
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