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Molecular and Cellular Biology, March 2002, p. 1881-1892, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1881-1892.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Heparan Sulfate Proteoglycans Are Ligands for Receptor Protein Tyrosine Phosphatase {sigma}

A. Radu Aricescu,1 Iain W. McKinnell,1 Willi Halfter,2 and Andrew W. Stoker1*

Neural Development Unit, Institute of Child Health, London WC1N 1EH, United Kingdom,1 Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 152612

Received 20 July 2001/ Returned for modification 12 October 2001/ Accepted 24 December 2001

RPTP{sigma} is a cell adhesion molecule-like receptor protein tyrosine phosphatase involved in nervous system development. Its avian orthologue, known as cPTP{sigma} or CRYP{alpha}, promotes intraretinal axon growth and controls the morphology of growth cones. The molecular mechanisms underlying the functions of cPTP{sigma} are still to be determined, since neither its physiological ligand(s) nor its substrates have been described. Nevertheless, a major class of ligand(s) is present in the retinal basal lamina and glial endfeet, the potent native growth substrate for retinal axons. We demonstrate here that cPTP{sigma} is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (HSPGs) agrin and collagen XVIII. These molecules interact with high affinity with cPTP{sigma} in vitro, and this binding is totally dependent upon their heparan sulfate chains. Using molecular modelling and site-directed mutagenesis, a binding site for heparin and heparan sulfate was identified in the first immunoglobulin-like domain of cPTP{sigma}. HSPGs are therefore a novel class of heterotypic ligand for cPTP{sigma}, suggesting that cPTP{sigma} signaling in axons and growth cones is directly responsive to matrix-associated cues.

* Corresponding author. Mailing address: Neural Development Unit, Institute of Child Health, 30 Guilford St., London WC1N 1EH, United Kingdom. Phone: 44-20-79052244. Fax: 44-20-78314366. E-mail: a.stoker{at}ich.ucl.ac.uk.

Molecular and Cellular Biology, March 2002, p. 1881-1892, Vol. 22, No. 6
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.6.1881-1892.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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