Haque, Aftabul, Andersen, J. N., Salmeen, A., Barford, D., Tonks, N. K. (September 2011) Conformation-Sensing Antibodies Stabilize the Oxidized Form of PTP1B and Inhibit Its Phosphatase Activity. Cell, 147 (1). pp. 185-198. ISSN 0092-8674
Abstract
Summary Protein tyrosine phosphatase 1B (PTP1B) plays important roles in downregulation of insulin and leptin signaling and is an established therapeutic target for diabetes and obesity. PTP1B is regulated by reactive oxygen species (ROS) produced in response to various stimuli, including insulin. The reversibly oxidized form of the enzyme (PTP1B-OX) is inactive and undergoes profound conformational changes at the active site. We generated conformation-sensor antibodies, in the form of single-chain variable fragments (scFvs), that stabilize PTP1B-OX and thereby inhibit its phosphatase function. Expression of conformation-sensor scFvs as intracellular antibodies (intrabodies) enhanced insulin-induced tyrosyl phosphorylation of the β subunit of the insulin receptor and its substrate IRS-1 and increased insulin-induced phosphorylation of PKB/AKT. Our data suggest that stabilization of the oxidized, inactive form of PTP1B with appropriate therapeutic molecules may offer a paradigm for phosphatase drug development.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > antibodies diseases & disorders > nutritional and metabolic diseases > diabetes |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Tonks lab CSHL Cancer Center Program > Signal Transduction |
| Depositing User: | CSHL Librarian |
| Date: | 30 September 2011 |
| Date Deposited: | 12 Oct 2011 20:58 |
| Last Modified: | 16 Oct 2015 13:57 |
| PMCID: | PMC3200309 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/15557 |
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