ABSTRACT

Protein-tyrosine phosphatases (PTPases) play an essential role in the regulation of cell activation, proliferation, and differentiation. A major subfamily of these enzymes is the transmembrane-type PTPases that contain extracellular regions comprised of Ig-like and fibronectin type III (FN-III)-like domains. Characterization of the human transmembrane PTPase (HPTP) revealed the existence of multiple HPTP isoforms that vary in their extracellular regions. The full-length HPTP isoform has an extracellular region containing three Ig-like and eight FN-III-like domains connected via a transmembrane peptide to an intracellular region with two PTPase domains, whereas another isoform lacks four of the eight FN-III like domains. Furthermore, other HPTP isoforms exist that lack 9 amino acids within the second Ig-like domain and 4 amino acids at the junction of the second and third Ig-like domains or 9 amino acids within the fifth FN-III-like domain. Reverse transcription polymerase chain reaction analysis demonstrated that HPTP isoforms lacking these short peptides are expressed in kidney, whereas isoforms containing these peptides are expressed in the brain. Analysis of HPTP biosynthesis demonstrated that HPTP is expressed as a complex of two noncovalently associated subunits derived from a proprotein and that the HPTP ectodomain is shed from the cell surface. Mutational analysis of the HPTP proprotein cleavage site revealed the existence of two or three functional and overlapping furin-like endoprotease cleavage sites.

FOOTNOTES

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This work was supported by Grant CA55547 from the National Institutes of Health (to M. S.), a post-doctoral fellowship award from the Fundación Ramón Areces (Spain) (to R. P.), a Fulbright fellowship award from the Ministerio de Educación y Ciencia (Spain) (to C. S. P.), and a Pew Scholar in the Biomedical Sciences Award (to M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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The abbreviations used are: PTPase, protein-tyrosine phosphatase; LAR, leukocyte common antigen-related protein; HPTP, human protein-tyrosine phosphatase ; MPTP, murine protein-tyrosine phosphatase ; FN-III, fibronectin type III; PCR, polymerase chain reaction; RT-PCR, reverse transcription PCR; mAb, monoclonal antibody; PAGE, polyacrylamide gel electrophoresis; bp, base pair(s); kb, kilobase(s).

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