Density enhanced protein tyrosine phosphatases

Details Density enhanced protein tyrosine phosphatases Density enhanced protein tyrosine phosphatases

1999-11-23

2003-04-22

Mertz, Prema (Department: 1652)

Chemistry: natural resins or derivatives; peptides or proteins;

Proteins, i.e., more than 100 amino acid residues

C536S023200, C435S069100, C435S325000, C435S320100, C435S071100, C435S071200, C435S471000, C435S252300, C435S254110, C435S196000

Reexamination Certificate

active

06552169

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to purified and isolated protein tyrosine phosphatase enzymes (PTPs) and polynucleotides encoding the same. PTPs of the invention are characterized by upregulated mRNA transcription and/or translation, or post-translational modification leading to increased total cellular enzyme activity as a function of increased cellular contact with neighboring cells. Such density enhanced PTPs are referred to as DEPTPs. An illustrative human Type III receptor-like density-enhanced protein tyrosine phosphatase has been designated huDEP-1.
BACKGROUND OF THE INVENTION
Protein tyrosine phosphorylation is an essential element in signal transduction pathways which control fundamental cellular processes including growth and differentiation, cell cycle progression, and cytoskeletal function. Briefly, the binding of growth factors, or other ligands, to a cognate receptor protein tyrosine kinase (PTK) triggers autophosphorylation of tyrosine residues in the receptor itself and phosphorylation of tyrosine residues in the enzyme's target substrates. Within the cell, tyrosine phosphorylation is a reversible process; the phosphorylation state of a particular tyrosine residue in a target substrate is governed by the coordinated action of both (PTKs), catalyzing phosphorylation, and protein tyrosine phosphatases (PTPs), catalyzing dephosphorylation.
The PTPs are a large and diverse family of enzymes found ubiquitously in eukaryotes [Charbonneau and Tonks,
Ann.Rev. Cell Biol
. 8:463-493 (1993)]. Structural diversity within the PTP family arises primarily from variation in non-catalytic (potentially regulatory) sequences which are linked to one or more highly conserved catalytic domains. In general, soluble cytoplasmic PTP forms are termed non-receptor PTPs and those with at least one non-catalytic region that traverses the cell membrane are termed receptor-like PTPs (RPTPs).
A variety of non-receptor PTPs have been identified which characteristically possess a single catalytic domain flanked, by non-catalytic sequences. Such non-catalytic sequences have been shown to include, among others, sequences homologous to cytoskeletal-associated proteins [Yang and Tonks,
Proc.Natl.Acad.Sci
. (
USA
) 88:5949-5953 (1991)] or to lipid binding proteins [Gu, et al.,
Proc.Natl.Acad.Sci
. (
USA
) 89:2980-2984 (1992)], and/or sequences that mediate association of the enzyme with specific intracellular membranes [Frangioni et al.,
Cell
68:545-560 (1992)], suggesting that subcellular localization may play a significant role in regulation of PTP activity.
Analysis of non-catalytic domain sequences of RPTPs suggests their involvement in signal transduction mechanisms. However, binding of specific ligands to the extracellular segment of RPTPs has been characterized in only a few instances. For example, homophilic binding has been demonstrated between molecules of PTP&mgr; [Brady-Kalnay, et al.,
J. Cell. Biol
. 122:961-972 (1993)] i.e., the ligand for PTP&mgr; expressed on a cell surface is another PTP&mgr; molecule on the surface of an adjacent cell. Little is otherwise known about ligands which specifically bind to, and modulate the activity of, the majority of RPTPs.
Many receptor-like PTPs comprise an intracellular carboxyl segment with two catalytic domains, a single transmembrane domain and an extracellular amino terminal segment [Krueger et al.,
EMBO J
. 9:3241-3252 (1990)]. Subclasses of RPTPs are distinguished from one another on the basis of categories or “types” of extracellular domains [Fischer, et al.,
Science
253:401-406 (1991)]. Type I RPTPs have a large extracellular domain with multiple glycosylation sites and a conserved cysteine-rich region. CD45 is a typical Type I RPTP. The Type II RPTPs contain at least one amino terminal immunoglobulin (Ig)-like domain adjacent to multiple tandem fibronectin type III (FNIII)-like repeats. Similar repeated FNIII domains, believed to participate in protein:protein interactions, have been identified in receptors for IL2, IL4, IL6, GM-CSF, prolactin, erythropoietin and growth hormone [Patthy,
Cell
61:13-14 (1992)]. The leukocyte common antigen-related PTP known as LAR exemplifies the Type II RPTP structure [Streuli et al.,
J.Exp.Med
. 168:1523-1530 (1988)], and, like other Type II RPTPs, contains an extracellular region reminiscent of the NCAM class of cellular adhesion molecules [Edelman and Crossin,
Ann.Rev.Biochem
. 60:155-190 (1991)]. The Type III RPTPs, such as HPTP&bgr; [Krueger et al.,
EMBO J
. 9:3241-3252 (1990)], contain only multiple tandem FNIII repeats in the extracellular domain. The Type IV RPTPs, for example RPTP&agr; [Krueger et al. (1990) supra], have relatively short extracellular sequences lacking cysteine residues but containing multiple glycosylation sites. A fifth type of RPTP, exemplified by PTP&ggr; [Barnes, et al.,
Mol.Cell.Biol
. 13:1497-1506 (1993)] and PTP&zgr; [Krueger and Saito,
Proc.Natl.Acad.Sci
. (
USA
) 89:7417-7421 (1992)], is characterized by an extracellular domain containing a 280 amino acid segment which is homologous to carbonic anhydrase (CAH) but lacks essential histidine residues required for reversible hydration of carbon dioxide.
FNIII sequences characteristically found in the extracellular domains of Type II and Type III RPTPs comprise approximately ninety amino acid residues with a folding pattern similar to that observed for Ig-like domains [Bork and Doolittle,
Proc.Nail.Acad.Sci
(
USA
) 89:8990-8994 (1992)]. Highly conserved FNIII sequences have been identified in more than fifty different eukaryotic and prokaryotic proteins [Bork and Doolittle,
Proc.Natl.Acad.Sci
. (
USA
) 89:8990-8994 (1992)], but no generalized function has been established for these domains. Fibronectin itself contains fifteen to seventeen FNIII domain sequences, and it has been demonstrated that the second FNIII domain (FNIII
2
) contains a binding site for heparin sulphate proteoglycan [Schwarzbauer,
Curr.Opin.Cell Biol
. 3:786-791 (1991)] and that FNIII
13
and FNIII
14
are responsible for heparin binding through ionic interactions [Schwarzbauer,
Curr. Opin. Cell Biol
. 3:786-791 (199 1)]. Perhaps the best characterized interaction for a fibronectin FNIII domain involves FNIII
10
which is the major site for cell adhesion [Edelman and Crossin,
Ann.Rev.Biochem
60:155-190 (1991); Leahy, et al.,
Science
258:987-991 (1992); Main, et al.,
Cell
71:671-678 (1992)]. FNIII
10
contains the amino acid sequence Arg-Gly-Asp (RGD) which is involved in promoting cellular adhesion through binding to particular members of the integrin superfamily of proteins.
Characteristics shared by both the soluble PTPs and the RPTPs include an absolute specificity for phosphotyrosine residues, a high affinity for substrate proteins, and a specific activity which is one to three orders of magnitude in excess of that of the PTKs in vitro [Fischer, et al.,
Science
253:401-406 (1991); Tonks,
Curr.Opin.Cell.Biol
. 2:1114-1124 (1990)]. This latter characteristic suggests that PTP activity may exert an antagonistic influence on the action of PTKs in vivo, the balance between these two thus determining the level of intracellular tyrosine phosphorylation. Supporting a dominant physiological role for PTP activity is the observation that treatment of NRK-1 cells with vanadate, a potent inhibitor of PTP activity, resulted in enhanced levels of phosphotyrosine and generation of a transformed cellular morphology [Klarlund,
Cell
41:707-717 (1985)]. This observation implies potential therapeutic value for PTPs and agents which modulate PTP activity as indirect modifiers of PTK activity, and thus, levels of cellular phosphotyrosine.
Recent studies have highlighted aspects of the physiological importance of PTP activity. For example, mutations in the gene encoding a non-receptor hematopoietic cel

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