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Characterization of the Receptor Protein Tyrosine Phosphatase Gene Product PTP: Binding and Activation by Triphosphorylated Nucleosides¹

Jefferson Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107

A full-length cDNA for a novel isoform of the human receptor tyrosine phosphatase gene (PTPRG) was overexpressed in Sf9 insect cells, and the gene product, PTP, was purified and characterized. The protein was expressed as a M_r 185,000 protein accompanied by a M_r 120,000 putative cleavage product on SDS-PAGE analysis. The protein undergoes N-linked glycosylation and constitutive phosphorylation of serine residues. When assayed for tyrosine-specific phosphatase activity, PTP dephosphorylated myelin basic protein at a pH optimum of 7.5 and a K_m of 12.6 µM; reduced carboxyamidomethylated and maleylated lysozyme (RCM-lysozyme) at a pH optimum of 6.0 and a K_m of 12 µM; and p-nitrophenylphosphate with a pH optimum of 5.5 and a K_m of 3.5 mM. Phosphatase activity was inhibited by ZnCl₂ and sodium orthovanadate; Mg²⁺, Mn²⁺, and Ca²⁺ ions were ineffective. The partially purified form of the enzyme was allosterically activated by triphosphorylated nucleosides, with a preference for purines. This activation was prevented by Mg²⁺ addition and did not occur when a purified form of the enzyme was utilized, suggesting that its activation depends on specific activating factors or conformational constraints. Interestingly, PTP protein was specifically bound by an ATP-agarose matrix through its intracellular domain, suggesting a link between binding of nucleotides and activation of the phosphatase.

¹ This work was supported in part by National Cancer Institute Grants CA51083 and CA39860 and by a gift from R. R. M. Carpenter III and Mary K. Carpenter. J. M. was supported by National Cancer Institute Training Grant T32-CA09662. C. S. is a recipient of a Dottorato di Ricerca in Biologia e Patologia Molecolare e Cellulare from the University of Verona, Verona, Italy.

² To whom requests for reprints should be addressed, at Jefferson Cancer Institute, Jefferson Medical College, BLSB, Room 1008, 233 South 10th Street, Philadelphia, PA 19107.

Received 8/17/95. Accepted 9/ 5/95.

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