PTP 1D: a novel protein tyrosine phosphatase

Details PTP 1D: a novel protein tyrosine phosphatase PTP 1D: a novel protein tyrosine phosphatase

1999-03-31

2003-04-15

Kunz, Gary (Department: 1647)

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...

C530S350000, C530S388100, C530S388260

Reexamination Certificate

active

06548641

ABSTRACT:

2. BACKGROUND OF THE INVENTION
2.1. Field of the Invention
This invention, in the fields of biochemistry and cell and molecular biology, relates to a novel protein tyrosine phosphatase (PTP) termed PTP 1D. Included is the PTP 1D protein, nucleic acid constructs coding therefor, recombinant expression vectors comprising the nucleic acid construct, cells containing or expressing the recombinant expression vectors, methods for producing and identifying PTP 1D protein and DNA constructs, antibodies specific for PTP 1D protein and glycoprotein, and methods for screening compounds capable of binding to the inhibiting or stimulating protein tyrosine phosphatase enzymatic activity of PTP 1D.
2.2. Description of the Background Art
2.2.1. Introduction
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 has attracted much interest since the discovery that many oncogene products and growth factor receptors possess intrinsic protein tyrosine kinase (PTKase or PTK) 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)).
The phosphorylation of protein tyrosine residues is a dynamic process with competing phosphorylation and dephosphorylation reactions. These processes are regulated by the reciprocal actions of PTKs, which catalyze tyrosine phosphorylation, and protein tyrosine phosphatases (PTPases or PTPs), which specifically dephosphorylate tyrosine residues of phosphorylated proteins. The net level of tyrosine phosphorylation of intracellular proteins is thus determined by the balance of PTK and PTP enzymatic activities. (Hunter, T.,
Cell
58:1013-1016 (1989)).
2.2.2. Protein Tyrosin Kinases
PTKs comprise a large family of proteins, including many growth factor receptors and potential oncogenes which share ancestry with, but nevertheless differ from, serine/threonine-specific protein kinases (Hanks et al.,
Science
241:42-52 (1988)). Many PTKs have been linked to initial signals in the induction of the cell cycle (Weaver et al.,
Mol. Cell. Biol.
11:4415-4422 (1991)).
Most of our current understanding of mechanism underlying changes in PTKs comes from receptor-type PTKs (RPTKs) having a transmembrane topology. The binding of a specific ligand to the extracellular domain of an RPTK is thought to induce oligomerization, increasing the enzymatic (kinase) activity and activation of the signal transduction pathways (Ullrich et al., supra). Dysregulation of kinase activity through mutation or overexpression is a well ——established mechanism underlying cell transformation (Hunter et al., 1985supra; Ullrich et al., supra).
2.2.3. Protein Tyrosine Phosphatases
The protein phosphatases comprise at least two separate and distinct families (Hunter, T., 1989, supra): protein serine/threonine phosphatases and protein tyrosine phosphatases (PTPs). The PTPs are themselves a family, containing at least two subgroups. The first subgroup comprises low molecular weight, intracellular enzymes that contain a single conserved catalytic phosphatase domain. Members of this subgroup include:
(1) placental PTP
1
B (Charbonneau et al.,
Proc. Natl. Acad. Sci. USA
86:5252-5256 (1989); Chernoff et al.,
Proc. Natl. Acad. Sci. USA
87:2735-2789 (1989));
(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
87:5201-1502 (1990));
(4) neuronal phosphatase (STEP) (Lomborso et al.,
Proc. Natl. Acad. Sci. USA
88:7242-7246 (1991)); and
(5) cytoplasmic phosphatases that contain a region of homology to cytoskeletal proteins (Gu et al.,
Proc Natl. Acad. Sci. USA
88:5867-57871 (1991); Yang et al.,
Proc. Natl. Acad. Sci. USA
88:5949-5953 (1991)).
Since the first PTP was purified, sequenced and cloned, additional potential PTPs have been identified at a rapid pace, and the number continues to grow steadily. The large number of known members of the PTP family suggests that there may be specificity in PTP-RPTK interactions. A cDNA encoding a novel PTP designated PTP 1C was cloned form several sources (Shen, S. -H. et al.,i Nature 352:736-739 (1991); Plutzky, J. et al.,
Proc. Natl. Acad. Sci. USA
89:1123—(1992); Yi, T., et al.,
Mol. Cell Biol.
12:836-846 (1992 ); Matthews, R. J. et al.,
Molec. Cell. Biol.
12:2396—(1992)). The PTP 1C protein has a single catalytic domain and a pair of N-terminally located src-homology regions, termed SH2, suggesting that PTK activity could be directly regulated by SH2 domain-mediated interaction with a PTP.
The second PTP subgroup includes the high molecular weight, receptor-linked PTPs, termed RPTPs. RPTPs consist of (a) an intracellular catalytic region, (b) a single transmembrane segment, an (c) a putative ligand-binding extracellular domain (Gebbink, M. F. et al.,
FEBS Lett.
290:123-130 (1991)). The structures and sizes of the putative “extracellular receptor” domains of various RPTPs are diverse, whereas the intracellular catalytic domains are highly conserved. All RPTPs have two tandemly duplicated catalytic phosphatase homology domains, with the exception of HPTPO, which has only one. Tsai et al.,
J. Biol. Chem.
266:10534-10543 (1991)).
One RPTP, originally named the leukocyte common antigen (LCA) (Ralph, S. J.,
EMBO J.
6:1251-1257 (1987)), has been known by other names, including T200 (Trowbridge et al.,
Eur. J. Immunol.
6:557-562 (1962 )), B220 for the B cell 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
, McMichael et al., eds., pp. 788-803, 1987). The LCA molecules comprise a family of high molecular weight glycoproteins expressed on the surface of all leukocytes and their hemopoietic progenitors (Thomas,
Ann. Rev. Immunol.
7:339-369 (1989)), and have remarkable sequence homology between animal species (Charbonneau et al.,
Proc. Natl. Acad. Sci. USA
85:7182-7186 (1988)). CD45 is thought to play a critical role in T cell activation. (For review, see: Weiss A.,
Ann. Rev. Genet.
25:487-510 (1991).) Thus, mutagenized T cell clones which did not express CD45 were functionally impaired in responding to stimulation via the T cell receptor (Weaver et al., 1991, supra). CD45 PTP activity played a role in the activation of pp56
kk
, 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 findings led to the hypothesis that T cell activation involved the phosphatase enzyme activating pp56
kk
by dephosphorylation of a C-terminal tyrosine residue.
Another RPTP, the leukocyte common antigen related molecule, LAR (Streuli et al.,
J. Exp. Med.
168:1523-1530 (1988)), was initially identified as an LCA homologue in which the intracellular catalytic region had two catalytic phosphatase homology domains (domains I and II). However, only domain I appeared to have phosphatase activity (Streuli et al.,
EMBO J.
9(8):2399-2407 (1990)). Chemically-induced LAR mutants (tyr
1379
→phe) were temperature-sensitive (Tsai et al.,
J. Biol. Chem.
266(16):10534-10543 (1991)).
A murine RPTP, designated mRPTP&mgr;, has an extracellular domain sharing structural motifs with LAR (Gebbink et al., supra). The human homologue of RPTP&mgr; was cloned, and the gene was localized to human chromosome 18. Two Drosophila PTPs, termed DLAR and DPTP were predicted based on the sequences of cDNA clones (Streuli et al.,
Proc. Natl. Acad. Sci. USA
86:8698-8702 (1989)). cDNA encoding another Drosophila RPTP, DPTP 99A, has also been cloned and characterized (Hariharan et al.,
Proc. Natl. Acad. S

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