TY - JOUR
T1 - Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase
AU - Desai, Dev M.
AU - Sap, Jan
AU - Schlessinger, Joseph
AU - Weiss, Arthur
N1 - Funding Information:
We are grateful to Dr. Shu Man Fu for providing MAb 235, Dr. Hanna Ostergaard and Dr. T. Higgins for providing the rabbit anti-CD45 cytoplasmic domain antisera, and Dr. D. Cool and Dr. Edmund Fischer for providing the human CD45RO cDNA. We would also like to thank Dr. Andrew Chan for critically reviewing this manuscript. This work was supported in part by a grant from the National Institutes of Health (NIH) (to A. W.). D. M. D. is supported by the NIH Medical Scientist Training Program.
PY - 1993/5/7
Y1 - 1993/5/7
N2 - CD45, a transmembrane protein tyrosine phosphatase (PTPase), is required for TCR signaling. Multiple CD45 isoforms, differing in the extracellular domain, are expressed in a tissue- and activation-specific manner, suggesting an important function for this domain. We report that a chimeric protein in which the extracellular and transmembrane domains of CD45 are replaced with those of the EGF receptor (EGFR) is able to restore TCR signaling in a CD45-deficient cell. Thus, the cytoplasmic domain of CD45 is necessary and sufficient for TCR signal transduction. Moreover, EGFR ligands functionally inactivate the EGFR-CD45 chimera in a manner that is dependent on dimerization of the chimeric protein. Inactivation of EGFR-CD45 chimera function results in the loss of TCR signaling, indicating that CD45 function is continuously required for TCR-mediated proximal signaling events. These results suggest that ligand-mediated regulation of receptor-PTPases may have mechanistic similarities with receptor tyrosine kinases.
AB - CD45, a transmembrane protein tyrosine phosphatase (PTPase), is required for TCR signaling. Multiple CD45 isoforms, differing in the extracellular domain, are expressed in a tissue- and activation-specific manner, suggesting an important function for this domain. We report that a chimeric protein in which the extracellular and transmembrane domains of CD45 are replaced with those of the EGF receptor (EGFR) is able to restore TCR signaling in a CD45-deficient cell. Thus, the cytoplasmic domain of CD45 is necessary and sufficient for TCR signal transduction. Moreover, EGFR ligands functionally inactivate the EGFR-CD45 chimera in a manner that is dependent on dimerization of the chimeric protein. Inactivation of EGFR-CD45 chimera function results in the loss of TCR signaling, indicating that CD45 function is continuously required for TCR-mediated proximal signaling events. These results suggest that ligand-mediated regulation of receptor-PTPases may have mechanistic similarities with receptor tyrosine kinases.
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U2 - 10.1016/0092-8674(93)90141-C
DO - 10.1016/0092-8674(93)90141-C
M3 - Article
C2 - 8490965
AN - SCOPUS:0027266773
SN - 0092-8674
VL - 73
SP - 541
EP - 554
JO - Cell
JF - Cell
IS - 3
ER -