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Molecular and Cellular Biology, March 2007, p. 1795-1808, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.00535-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Dimerization of Protein Tyrosine Phosphatase {sigma} Governs both Ligand Binding and Isoform Specificity{triangledown}

Simon Lee, Clare Faux, Jennifer Nixon, Daniel Alete, John Chilton,{dagger} Muhamed Hawadle, and Andrew W. Stoker*

Neural Development Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom

Received 27 March 2006/ Returned for modification 27 April 2006/ Accepted 25 November 2006

Signaling through receptor protein tyrosine phosphatases (RPTPs) can influence diverse processes, including axon development, lymphocyte activation, and cell motility. The molecular regulation of these enzymes, however, is still poorly understood. In particular, it is not known if, or how, the dimerization state of RPTPs is related to the binding of extracellular ligands. Protein tyrosine phosphatase {sigma} (PTP{sigma}) is an RPTP with major isoforms that differ in their complements of fibronectin type III domains and in their ligand-binding specificities. In this study, we show that PTP{sigma} forms homodimers in the cell, interacting at least in part through the transmembrane region. Using this knowledge, we provide the first evidence that PTP{sigma} ectodomains must be presented as dimers in order to bind heterophilic ligands. We also provide evidence of how alternative use of fibronectin type III domain complements in two major isoforms of PTP{sigma} can alter the ligand binding specificities of PTP{sigma} ectodomains. The data suggest that the alternative domains function largely to change the rotational conformations of the amino-terminal ligand binding sites of the ectodomain dimers, thus imparting novel ligand binding properties. These findings have important implications for our understanding of how heterophilic ligands interact with, and potentially regulate, RPTPs.

* Corresponding author. Mailing address: Neural Development Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom. Phone: 020 7905 2244. Fax: 020 78314366. E-mail: astoker{at}ich.ucl.ac.uk.

{triangledown} Published ahead of print on 18 December 2006.

{dagger} Present address: Institute of Biomedical Science, Peninsula Medical School, Tamar Science Park, Research Way, Plymouth, Devon PL6 8BU, United Kingdom.

Molecular and Cellular Biology, March 2007, p. 1795-1808, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.00535-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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