PTP-S31: a novel protein tyrosine phosphatase

Details PTP-S31: a novel protein tyrosine phosphatase PTP-S31: a novel protein tyrosine phosphatase

1999-07-26

2002-12-10

Nolan, Patrick J. (Department: 1644)

Chemistry: natural resins or derivatives; peptides or proteins;

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

Blood proteins or globulins, e.g., proteoglycans, platelet...

C530S388260

Reexamination Certificate

active

06492495

ABSTRACT:

1. INTRODUCTION
The invention, in the fields of biochemistry and cell and molecular biology, relates to a novel protein tyrosine phosphatase (PTPase or PTP) protein or glycoprotein, termed PTP-S31, the use of such molecule in pharmaceutical preparations, and pharmaceutical compositions comprising PTP-S31 or functional derivatives thereof. This invention is also directed to nucleic acid molecules encoding the PTP-S31 protein or functional derivative, recombinant expression vectors carrying the nucleic acid molecules, cells containing the recombinant expression vectors, methods for production and identification of PTP-S31 or the DNA coding therefor, antibodies specific for PTP-S31, and methods for screening compounds capable of binding to and inhibiting or stimulating protein tyrosine phosphatase enzymatic activity of PTP-S31.
2. BACKGROUND OF THE INVENTION
Phosphorylation of proteins is a fundamental mechanism for regulating diverse cellular processes. While the majority of protein phosphorylation occurs at serine and threonine residues, phosphorylation at tyrosine residues is attracting a great deal of interest since the discovery that many oncogene products and growth factor receptors possess intrinsic protein tyrosine kinase activity. The importance of protein tyrosine phosphorylation in growth factor signal transduction, cell cycle progression and neoplastic transformation is now well established (Hunter et al.,
Ann. Rev. Biochem.
54:987-930 (1985), Ullrich et al.,
Cell
61 :203-212 (1990), Nurse,
Nature
344:503-508 (1990), Cantley et al.,
Cell
64:281-302 (1991)).
Biochemical studies have shown that phosphorylation on tyrosine residues of a variety of cellular proteins is a dynamic process involving competing phosphorylation and dephosphorylation reactions. The regulation of protein tyrosine phosphorylation is mediated by the reciprocal actions of protein tyrosine kinases (PTKases or PTKS) and protein tyrosine phosphatases (PTPs). The tyrosine phosphorylation reactions are catalyzed by PTKs. Tyrosine phosphorylated proteins can be specifically is dephosphorylated through the action of PTPS. The level of protein tyrosine phosphorylation of intracellular substances is determined by the balance of PTK and PTP activities. (Hunter, T.,
Cell
58:1013-1016 (1989)).
2.1. PTKs
The protein tyrosine kinases (PTKs; ATP:protein-tyrosine O-phosphotransferase, EC 2.7.1.112) are a large family of proteins that includes many growth factor receptors and potential oncogenes. (Hanks et al.,
Science
241:42-52 (1988)). Many PTKs have been linked to initial signals required for induction or the cell cycle (Weaver et al.,
Mol. and Cell. Biol.
11(9):4415-4422 (1991)). PTKs comprise a discrete family of enzymes having common ancestry with, but major differences from, serine/threonine-specific protein kinases (Hanks et al., supra). The mechanisms leading to changes in activity of PTKs are best understood in the case of receptor-type PTKs having a transmembrane topology (Ullrich et al. (1990) supra). The binding of specific ligands to the extracellular domain of members of receptor-type PTKs is thought to induce their oligomerization leading to an increase in tyrosine kinase activity and activation of the signal transduction pathways (Ullrich et al., (1990) supra). Deregulation of kinase activity through mutation or overexpression is a well-established mechanism for cell transformation (Hunter et al., (1985) supra; Ullrich et al., (1990) supra).
2.2. PTPS
The protein phosphatases are composed of at least two separate and distinct families (Hunter, T.(1989) supra) the protein serine/threonine phosphatases and the protein tyrosine phosphatases (PTPs; protein-tyrosine-phosphate phosphohydrolase, EC 3.13.48)). The PTPs are a family of proteins that have been classified into two subgroups. The first subgroup is made up of the low molecular weight, intracellular enzymes that contain a single conserved catalytic phosphatase domain. All known intracellular type PTPS contain a single conserved catalytic phosphatase domain.; Examples of the first group of PTPs include (1) placental PTP 1B (Charbonneau et al.,
Proc. Natl. Acad. Sci. USA
86:5252-5256 (1989); Chernoff et al.,
Proc. Natl. Acad. Sci. USA
87:2735-2789 (1990)), (2) T-cell PTP (Cool et al.
Proc. Natl. Acad. Sci. USA
86:5257-5261 (1989)), (3) rat brain PTP (Guan et al.,
Proc. Natl. Acad. Sci. USA
87:1501-1502 (1990)), (4) neuronal phosphatase (STEP) (Lombroso et al.,
Proc. Natl. Acad. Sci. USA
88:7242-7246 (1991)), and (5) cytoplasmic phosphatases that contain a region of homology to cytoskeletal proteins (Guet al.,
Proc. Natl. Acad. Sci. USA
88:5867-57871 (1991); Yang et al.,
Proc. Natl. Acad. Sci. USA
88:5949-5953 (1991)).
The second subgroup is made up of the high molecular weight, receptor-linked PTPs, termed RPTPs. RPTPs consist of (a) an intracellular catalytic region, (b) a single transmembrane segment, and (c) a putative ligand-binding extracellular domain. The structures and sizes of the putative ligand-binding extracellular “reqeptor” domains of RPTPs are quite divergent. In contrast, the intracellular catalytic regions of RPTPs are highly homologous. All RPTPs have two tandemly duplicated catalytic phosphatase homology domains, with the prominent exception of an RPTP termed HPTP&bgr;, which has only one catalytic phosphatase domain. (Tsai et al.,
J. Biol. Chem.
266:10534-10543 (1991)).
One example of RPTPs is a family of proteins termed leukocyte common antigens (LCA) (Ralph, S. J.,
EMBO J.
6:1251-1257 (1987)) which are high molecular weight glycoproteins expressed on the surface of all leukocytes and their hemopoietic progenitors (Thomas,
Ann. Rev. Immunol.
7:339-369 (1989)). A remarkable degree of similarity exists in the sequences of LCA from several species (Charbonneau et al.,
Proc. Natl. Acad. Sci. USA
85:7182-7186 (1988)). LCA has been referred to in the literature by different names, including T200 (Trowbridge et al.,
Eur. J. Immunol.
6:557-562 (1962)), B220 for the B lymphocyte form (Coffman et al.,
Nature
289:681-683 (1981)), the mouse allotypic marker Ly-5 (Komuro et al.,
Immunogenetics
1:452-456 (1975)), and more recently CD45 (Cobbold et al.,
Leucocyte Typing III,
A. J. McMichael et al., eds., pp. 788-803 (1987)).
CD45 appears to play a critical role in T cell activation (reviewed in Weiss A.,
Ann. Rev. Genet.
25:487-510 (1991)). For example, T-cell clones that were chemically mutagenized and selected for their failure to express CD45 had impaired responses to T-cell receptor stimuli (Weaver et al., supra). These T-cell clones were functionally defective in their responses to signals transmitted through the T cell antigen receptor, including cytolysis of appropriate targets, proliferation, and lymphokine production (Weaver et al., supra). Other studies indicate that the PTP activity of CD45 plays a role in the activation of pp 56
1ck
, a lymphocyte-specific PTK (Mustelin et al.,
Proc. Natl. Acad. Sci. USA
86:6302-6306 (1989); ostergaard et al.,
Proc. Natl. Acad. Sci. USA
86:8959-8963 (1989)). These authors hypothesized that the phosphatase activity of CD45 activates pp56
kk
by dephosphorylation of a C-terminal tyrosine residue, which may, in turn, be related to T-cell activation.
Another other example of an RPTP is the leukocyte common antigen related molecule (LAR), initially identified as a homologue of LCA (Streuli et al.,
J. Exp. Med.
168:1523-1530 (1988)). Although the intracellular catalytic region of the LAR molecule contains two catalytic phosphatase homology domains (domain I and domain II), mutational analyses suggested that only domain I had catalytic phosphatase activity, whereas domain II was enzymatically inactive (Streuli et al.,
EMBO J.
9(8):2399-2407 (1990)). Chemically induced LAR mutants having tyrosine at amino acid position 1379 changed to a phenylalanine were temperature-sensitive (Tsai et al.,
J. Biol. Chem.
266(16):10534-10543 (1991)).
A recently cloned mouse RPTP, designated mRPTP&mgr;, was found to have an extracellular domain that shared some struc

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