Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
2001-03-23
2003-12-16
Achutamurthy, Ponnathapu (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C435S252300, C435S320100, C435S071100, C536S023200
Reexamination Certificate
active
06664089
ABSTRACT:
BACKGROUND OF THE INVENTION
The intracellular phosphorylation of proteins is critical for a plethora of regulatory and signalling pathways in eukaryotic cells. Phosphorylation events can govern a wide range of cellular processes, including cell proliferation, differentiation, transcription, and morphology. An essential component of these signalling pathways is the ability of the cell to desensitize, recycle, and counteract phosphorylation signals. The cell primarily utilizes enzymes, termed phosphatases, which remove the phosphate on tyrosine, serine, and threonine side chains. The protein phosphatases are divided into three groups according to catalytic function: (1) protein phosphatases that dephosphorylate serine and threonine residues; (2) protein phosphatases which dephosphorylate tyrosine residues; and (3) dual specificity protein phosphatases which dephosphorylate serine, threonine and tyrosine residues.
Serine/threonine protein phosphatases are associated with the regulation of cholesterol biosynthesis, glycogen metabolism, muscle contractility, calcium ion channels, protein synthesis, regulation of the G2 to M transition of the cell cycle, regulation of glycolysis (6-phosphofructo-2-kinase and pyruvate kinase), glycogenolysis (phosphorylase kinase subunit), gluconeogenesis (fructose-2,6-bisphosphatase and pyruvate kinase), amino-acid degradation (phenylalanine hydroxylase), lipid metabolism (acetyl-CoA carboxylase), catecholamine synthesis (tyrosine hydroxylase) and protein synthesis (elongation factor 2).
Protein tyrosine phosphatases (PTPs) are a family of intracellular and integral membrane phosphatases that dephosphorylate tyrosine residues in proteins. PTPs have been identified in mammals, Drosophila and
Schiz. pombe
and are implicated in the control of normal and neoplastic growth and proliferation. They have also been found encoded by plasmids in bacteria of the genus Yersinia, where they are implicated in pathogenicity.
Dual specificity phosphatases hydrolyze phosphotyrosine, phosphothreonine, and phosphoserine residues (for a review, see, e.g., Fauman and Saper (1996)
Trends in Biochem.
21:412). This class of proteins is exemplified by the VH1 or vaccinia virus late HI gene protein, whose catalytic activity is required for vaccinia virus replication. A human homolog of VH1, VHR, has also been identified. VH1-like dual specificity phosphatase can also include the phosphatases PAC-1 and CL100/MKP-1, hVH-2/MKP-2, hVH-3, MKP-3, MKP-X, MKP-4, hVH-5, and M3/6 proteins. The PAC-1 and CL100 proteins hydrolyze phosphothreonine and phosphotyrosine residues on phosphorylated MAP (mitogen activated protein) kinases. In order to modulate signalling events, the activity and expression of dual specificity phosphatases can be finely regulated. For example, the PAC-1 and CL100 phosphatase can be induced by growth factors (Keyse, S (1995)
Biochim. Biophys. Acta
1265:152-160).
Thus, the function of dual specificity phosphatase proteins can be critical for the regulation of cellular processes such as proliferation and differentiation. Given the important biological roles and properties of phosphatases, there exists a need for the identification of novel genes encoding such proteins as well as for the discovery of modulators of such molecules for use in regulating a variety of normal and/or pathological cellular processes.
SUMMARY OF THE INVENTION
The present invention is based, in part, on the discovery of novel dual specificity phosphatases, referred to herein as “21117” or “38692” nucleic acid and protein molecules. The nucleotide sequence of cDNAs encoding 21117 and 38692 are shown in SEQ ID NOs:1 and 4, respectively and the amino acid sequences of 21117 and 38692 polypeptides are shown in SEQ ID NOs:2 and 5, respectively. In addition, the nucleotide sequence of the 21117 and 38692 coding regions are depicted in SEQ ID NOs:3 and 6, respectively.
Accordingly, in one aspect, the invention features a nucleic acid molecule that encodes a 21117 or 38692 protein or polypeptide, e.g., a biologically active portion of the 21117 or 38692 protein. In a preferred embodiment, the isolated nucleic acid molecule encodes a polypeptide having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5. In other embodiments, the invention provides isolated 21117 or 38692 nucleic acid molecules having the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:6. In still other embodiments, the invention provides nucleic acid molecules that are substantially identical (e.g., naturally occurring allelic variants) to the nucleotide sequence shown in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:6. In other embodiments, the invention provides a nucleic acid molecule that hybridizes under a stringent hybridization condition as described herein to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1, 3, 4, or 6, wherein the nucleic acid encodes a full length 21117 or 38692 protein or an active fragment thereof.
In a related aspect, the invention further provides nucleic acid constructs that include the 21117 or 38692 nucleic acid molecules described herein. In certain embodiments, the nucleic acid molecules of the invention are operatively linked to native or heterologous regulatory sequences. Also included are vectors and host cells containing the 21117 or 38692 nucleic acid molecules of the invention, e.g., vectors and host cells suitable for producing 21117 or 38692 nucleic acid molecules and polypeptides.
In another related aspect, the invention provides nucleic acid fragments suitable as primers or hybridization probes for the detection of 21117 or 38692-encoding nucleic acids.
In a preferred embodiment, a nucleic acid fragment includes at least one, two and preferably more, nucleotides from the sequence of nucleotide 1 to 2985 of SEQ ID NO:1.
In a preferred embodiment, a nucleic acid fragment includes at least one, preferably more, nucleotides from the sequence of nucleotides 1 to 432 of SEQ ID NO:4, or nucleotides 850 to 1114 of SEQ ID NO:4.
In still another related aspect, isolated nucleic acid molecules that are antisense to a 21117 or 38692 encoding nucleic acid molecule are provided.
In another aspect, the invention features 21117 or 38692 polypeptides and biologically active or antigenic fragments thereof that are useful, e.g., as reagents or targets in assays applicable to treatment and diagnosis of 21117 or 38692 mediated or related disorders, e.g., liver or hematopoietic cell associated disorders. In another embodiment, the invention provides 21117 or 38692 polypeptides having a 21117 or 38692 activity. Preferred polypeptides are 21117 or 38692 proteins including at least one dual specificity phosphatase catalytic domain, and, preferably, having a 21117 or 38692 activity, e.g., a 21117 or 38692 activity as described herein.
In other embodiments, the invention provides 21117 or 38692 polypeptides, e.g., a 21117 or 38692 polypeptide having the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:5; an amino acid sequence that is substantially identical to the amino acid sequence shown in SEQ ID NOs:2 or 5; or an amino acid sequence encoded by a nucleic acid molecule having a nucleotide sequence that hybridizes under a stringent hybridization condition as described herein to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOs:1, 3, 4, 6, wherein the nucleic acid encodes a full length 21117 or 38692 protein or an active fragment thereof.
In a related aspect, the invention provides 21117 or 38692 polypeptides or fragments operatively linked to non-21117 or 38692 polypeptides to form fusion proteins.
In another aspect, the invention features antibodies and antigen-binding fragments thereof, that react with, or more preferably, specifically bind 21117 or 38692 polypeptides.
In another aspect, the invention provides methods of screening for compounds that modulate the expression or activity of the 21117 or 38692 polypeptides or nucleic acids.
In still another aspect, the invention provides a process for modulating 211
Achutamurthy Ponnathapu
Millennium Pharmaceuticals Inc.
Millennium Pharmaceuticals Inc.
Pak Yong
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