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Received for publication November 22, 2004.
Revised December 17, 2004.
Accepted for publication January 3, 2005.
and PTP
IN LIVING CELLS
The interactions between the insulin receptor and the two highly homologous receptor-like protein-tyrosine-phosphatases PTP
and PTP
were studied in living cells by using bioluminescence resonance energy transfer. In HEK293 cells expressing the insulin receptor fused to luciferase and substrate-trapping mutants of PTP or PTP fused to the fluorescent protein Topaz, insulin induces an increase in resonance energy transfer that could be followed in real time in living cells. Insulin effect could be detected at very early time-points and was maximal less than 2 min after insulin addition. Bioluminescence resonance energy transfer saturation experiments indicate that insulin does not stimulate the recruitment of protein tyrosine-phosphatases molecules to the insulin receptor but rather induces conformational changes within pre-associated insulin receptor / protein tyrosine-phosphatases complexes. Physical pre-association of the insulin receptor with these protein tyrosine-phosphatases at the plasma membrane, in the absence of insulin, was also demonstrated by chemical cross-linking with a non-cell permeable agent. These data provide the first evidence that PTP and PTP associate with the insulin receptor in the basal state and suggest that these protein tyrosine-phosphatases may constitute important negative regulators of the insulin receptor tyrosine-kinase activity, by acting rapidly at the plasma membrane level.
Key words:
Insulin, Protein tyr Phosphatases, Src and other nonreceptor tyrosine kinases, Fluorescence techniques
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