Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-09-22
2001-04-10
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S252300, C435S325000, C435S471000, C435S320100, C435S069100, C435S070100, C435S071100, C435S071200, C530S350000, C536S023200
Reexamination Certificate
active
06214564
ABSTRACT:
BACKGROUND OF THE INVENTION
Protein tyrosine phosphorylation plays an important role in the regulation of cellular signal transduction, cell growth and differentiation. The level of tyrosine phosphorylation is controlled by the equilibrium of the activities of the protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) (Cantley, L. C. et al., 1991, Cell, 64, pp.281-302; Fischer, E. H. et al., 1991, Science, 253, pp.401-406; Alexander, D. R. and Cantrell, D. A., 1989, Immunol. Today, 10, pp.200-205; Tonks, N. K. and Charbonneau, H., 1989, Trends Biochem. Sci., 14, pp.497-500; Saito, H. and Streuli, M. 1991. Cell Growth And Differentiation, 2, pp.59-65; Gautier, J. et al., 1991, Cell, 67, pp.197-211; Zheng, X. M. et al., Nature, 359, pp.336-339). It is well documented that tyrosine kinase activities play an important role in the growth and the differentiation of bone cells. M-CSF and its receptor c-fms were shown to be crucial in osteoclast development. Recently Soriano et al. reported that disruption of c-src proto-oncogene, by homologous recombination, induced osteoporosis, that is characterized by the reduction of bone resorption due to impairment of osteoclastic function (Soriano, P. et al., 1991, Cell, 64, pp.693-702; Boyce, B. F. et al., 1992, J.Clin.Invest., 90, pp.1622-1627). In both in vivo and in vitro experiments it was demonstrated that FGF, IGF-I and IGF-II are important for the osteoblast functions. These findings suggest that the control of tyrosine phosphorylation is clearly important for bone cells.
As mentioned above, protein tyrosine phosphorylation is lightly balanced by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases. Treatment of bone cells with orthovanadate, a PTPase inhibitor, resulted in the stimulation of cell proliferation and the synthesis of bone collagen (Lau et al. Endocrinology, 1988, 123 pp. 2858-2867). In organ cultures, vanadate treatment inhibited the stimulation of bone resorption induced by treatment with PTH (Krieger and Tashjian, Endocrinology, 1983, 113. pp. 324-328). Taken together, these findings suggest that PTPases play an important function in bone cells.
SUMMARY OF THE DISCLOSURE
The polymerase chain reaction methodology was used to identify cDNA molecules for several PTPases in bone cells. One of these cDNA clones, named PTP-OB, encoded a novel member of the protein tyrosine phosphatase family. From human cDNA libraries, the entire open reading frame-encoding DNA was cloned for that protein. PTP-OB is composed of 1911 amino acid residues. Sequence analysis revealed two regions of hydrophobic amino acid residues that comprise a putative signal peptide and transmembrane domain, thus indicating PTP-OB as a receptor-like PTPase. The amino acid sequence of PTP-OB shows the best similarity to LAR and LAR related PTPases. As described for LAR, three immunoglobulin-like and eight fibronectin type III-like domains can be identified in the extracellular domain, and two tandem repeats of PTPase domains in the cytoplasmic region. The cDNA clones isolated from human brain library contained a deletion of 1227 bp that maintained the open reading frame, but coded for an extracellular region that was shorter by 409 amino acid residues and one with one amino acid substitution. Hybridization experiments revealed that PTP-OB was expressed as a 7.3 kilo base (kb) mRNA in both bone and brain tissues. The tissue distribution of PTP-OB transcript suggested that this receptor-like PTPase is involved in the growth and differentiation of osteoblasts and brain cells.
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Rodan Gideon A.
Rutledge Su Jane
Schmidt Azriel
Heber Sheldon O.
Kunz Gary L.
Landsman Robert S.
Merck & Co. , Inc.
Tribble Jack L.
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