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(12) United States Patent (10) Patent No.: US 6,939,952 B2 Zhao (45) Date of Patent: Sep USOO69399.52B2 (12) United States Patent (10) Patent No.: US 6,939,952 B2 Zhao (45) Date of Patent: Sep. 6, 2005 (54) PURIFIED AND ISOLATED PROTEIN ZERO Bowie et al. Deciphering the message in protein Sequences: RELATED (PZR) POLYPEPTIDE tolerance to amino acid substitutions. Science (1990) vol. 247, pp. 1306–1310.* (75) Inventor: Zhizhuang Zhao, Franklin, TN (US) GenBank Accession if AAD55347. (73) Assignee: Vanderbilt University, Nashville, TN Burshtyn et al., “Regulation Through Inhibitory Receptors: (US) Lessons from Natural Killer Cells”, Trends in Cell Biology, (*) Notice: Subject to any disclaimer, the term of this vol. 7, p. 473–479, (Dec., 1997). patent is extended or adjusted under 35 Choe, “Packing of Myelin Protein Zero, Neuron, vol. 17, p. U.S.C. 154(b) by 69 days. 363-365, (Sep., 1996). Harding, “From the Syndrome of Charcot, Marie and Tooth (21) Appl. No.: 10/095,131 to Disorders of Peripheral Myelin Proteins,” Brain, vol. 118, (22) Filed: Mar 11, 2002 p. 809–818, (Nov., 1995). Saxton et al., “Abnormal Mesoderm Patterning in Mouse (65) Prior Publication Data Embryos Mutant for the SH2 Tyrosine Phosphatase Shp-2.” US 2003/0171565 A1 Sep. 11, 2003 The EMBO Journal, vol. 16 (No. 9), p. 2352–2364, (Nov., 1997). Related U.S. Application Data Tidow et al., “SH2-Containing Protein Tyrosine Phos (62) Division of application No. 09/430.503, filed on Oct. 29, phatases SHP-1 and SHP-2 are Dramatically Increased at 1999, now Pat. No. 6,355,786. the Protein Level in Neutrophils from Patients with Severe (60) Provisional application No. 60/106,459, filed on Oct. 30, Congenital Neutropenia (Kostmann's Syndrome), Experi 1998. mental Hematology, vol. 27 (No. 6), p. 1038-1045, (Nov., (51) Int. Cl. .................................................. C07K 1100 1999). (52) U.S. Cl. ..................... 530/350; 435/69.1, 536/23.1; Unkeless et al., “Inhibitory Receptors, ITIM Sequences and 536/23.5 Phosphatases,” Current Opinion in Immunology, Vol. 9, p. (58) Field of Search .......................................... 530/350 338-343, (Nov., 1997). (56) References Cited Zhao et al., “Altered Expression of Protein-Tyrosine Phos phatase 2C in 293 Cells Affects Protein Tyrosine Phospho U.S. PATENT DOCUMENTS rylationn and Mitogen-Activated Protein Kinase Activa 5,352.660 A 10/1994 Pawson tion,” The Journal of Biological Chemistry, vol. 270 (No. 5,580,979 A 12/1996 Bachovchin 20), p. 11765–11766, (May 19, 1995). 5,589,375 A 12/1996 Ulrich et al. 5,624,816. A 4/1997 Carraway et al. Zheng et al., “Concanavalin A Protects Hair Cells Against 5,693.488 A 12/1997 Fang et al. Gentamicin Ototoxicity in Rat Cochlear Explant Cultures,” 5,723,593 A 3/1998 Lebo et al. Journal of Neurobiology, vol. 39 (No. 1), p. 29-40, (Apr., 5,739.278 A 4/1998 Daum et al. 1999). 5,753,687. A 5/1998 Mjalli et al. 5,776,902 A 7/1998 Bachovchin * cited by examiner 5,786,152 A 7/1998 Marengere et al. 2003/O135034 A1 7/2003 Baker et al. ............... 536/23.2 Primary Examiner Ulrike Winkler FOREIGN PATENT DOCUMENTS (74) Attorney, Agent, or Firm-Jenkins, Wilson & Taylor, WO WO 94/08600 4/1994 P.A. WO WO 96/26961 9/1996 WO WO 96/4.0113 12/1996 (57) ABSTRACT WO WO 96/40276 12/1996 WO WO 97/32598 9/1997 Isolated and purified proteins and nucleic acids including a WO WO 98/04712 2/1998 novel member of the immunoglobulin Super-family charac terized as having SHP-2 binding activity and cell Signaling OTHER PUBLICATIONS activity and called protein zero related or PZR, and cDNA Lazar et al. Transforming growth factor alpha: mutation of encoding the Same. Recombinant host cells, recombinant aspartic acid 47 and leucine 48 results in different biological nucleic acids and recombinant proteins are also disclosed, activities. Molecular and Cellular Biology (1988) vol. 8, No. along with methods of producing each. Isolated and purified 3, pp. 1247–1252.* antibodies to PZR, and methods of producing the Same, are BurgeSS et al. PoSSible dissociation of the heparin-binding also disclosed. PZR is characterized as having SHP-2 bind and mitogenic activities of heparin-binding (acidic fibro ing activity and cell Signaling activity and thus, therapeutic blast) growth factor-1 from its receptor-binding activities methods involving these activities are also disclosed. by Site-directed mutagenesis of a Single lysine residue. Journal of Cell Biol. 6 Claims, 5 Drawing Sheets U.S. Patent Sep. 6, 2005 Sheet 2 of 5 US 6,939,952 B2 I (r. 12. It R2 A p Sa?h phi () (32. A - H - - - - > - - O. A - C fill C. A. A. A (3 a UD A E a < r < - - - - - - - - - - D - - D - - - - D. D. - C ( > H H A U.S. Patent Sep. 6, 2005 Sheet 4 of 5 US 6,939,952 B2 Signal Scquence Extracellular s s s s Transin embranc Intraccllular Y241 F241. Y241. F241 Y263 -Y263 263 F263 FIGURE 4 U.S. Patent Sep. 6, 2005 Sheet 5 of 5 US 6,939,952 B2 SH2 PTP 32 138 459 SHP-2 NN K32 38 459 SHP-2(R-K) (NN H SHP-2(R38-K) (NN32 K138 m59 459 ASHP-2 Dmi 32 138 459 SHP-2(C-S) (NN m SHP-2(C-S, R32-K) 32 138 459 SHP-2(C-S, R38-K) NN 459 ASHP-2(C-S) Om Myr-ASHP-2(C-S) 2SH2 FIGURE 5 US 6,939,952 B2 1 2 PURIFED AND SOLATED PROTEIN ZERO (1995) Adv: in Protein Phosphatases 9:297-317; Streuli, M. RELATED (PZR) POLYPEPTIDE (1996) Curr. Opinion in Cell Biol. 183: 182-188; Scharenberg, A. M. and Kinet, J. P. (1996) Cell 87.961–964; PRIORITY APPLICATION INFORMATION Tonks, N. K., & Neel, B. G. (1996) Cell 87:365–368; This application is a divisional of U.S. patent application Frearson, J. A. and Alexander, D. R. (1997) Bioessays Ser. No. 09/430,503, filed Oct. 29, 1999 and now issued as 19:417-427; Ulyanova, T., Blasioli, J., and Thomas, M. L. U.S. Pat. Ser. No. 6,355,786 B1, claiming priority to U.S. (1997) Immunolog. Res. 16:101-113; Byon, J. C., et al. Provisional Application Ser. No. 60/106,459 filed Oct. 30, (1997) Proc. Soc. Exp. Biol. & Med. 216:1-20; Neel, B. G. 1998, the entire contents of both of which are herein and Tonks, N. K. (1997) Curr. Opin. Cell. Biol. 9:193-204. incorporated by reference. SHP-1 and SHP-2 share nearly 60% overall sequence identity and are regulated in Similar manners. Nevertheless, GRANT STATEMENT in many Systems, they have distinct physiological functions. SHP-1 has a negative role in proliferation of hematopoietic This work was supported by National Institutes of Health cells whereas SHP-2 is a positive transducer of growth (NIH) grants HL57393, CA75218 and CA-69485. Thus, the 15 factor Signal transduction. This distinction in functions is U.S. Government has certain rights in the invention. presumably due to different physiological targets. Recently, a number of putative substrates of SHP-1 and TECHNICAL FIELD SHP-2 have been identified. Xiao, S., et al. (1994) J. Biol. The present invention relates generally to isolated and Chem. 269:21244-21248; Millarski, K. L. and Saltiel, A. L. purified proteins that modulate SHP-2 biological activity (1994) J. Biol. Chem. 269:21239–21243; Noguchi, T., et al. and modulate cell Signaling, and to nucleic acids encoding (1994) Mol. Cell. Biol. 14:6674-6682; Yamauchi, K., et al. the same. More particularly, the present invention relates to (1995) Proc. Natl. Acad. Sci. U.S.A. 92:664-668; Yamauchi, an isolated and purified transmembrane protein designated K., et al. (1995).J. Biol. Chem. 270:17716–17722; Frearson, as “protein zero related” or “PZR' that binds the tyrosine J. A., Yi, T., and Alexander, D. R. (1996) Eur: J. Immunol. phosphatase SHP-2, and an isolated and purified polynucleic 25 26:1539–1543; Valiante, N. M., et al. (1996) J. Exp. Med. acid encoding the Same. 184:2243-2250; Carlberg, K. and Rohrschneider, L. R. (1997) J. Biol. Chem. 272:15943–15950; Ruff, S.J., Chen, K., and Cohen S. (1997).J. Biol. Chem. 272:1263–1267; Gu, H., Griffin, J. D., and Neel, B. G. (1997) J. Biol. Chem. Table of Abbreviations 272:16421-16430; Jiao, H., et al. (1997) Exp. Hematol. BSA Bovine serum albumin 25:592–600. One of them, designated as SIRP or SHPS-1, EGF epidermal growth factor has been cloned (Kharitonenkov, A., et al. (1997) Nature EST expressed sequence tags 38.6:181–186; Fujioka, Y., et al. (1996) Mol. Cell. Biol. FeyRB an ITIM-containing hematopoietic cell protein 16:6887-6899). Overexpression of catalytically inactive GC-MS gas chromatography-mass spectroscopy 35 HAT cell culture media comprising hypoxanthine, mutants of SHP-1 and SHP-2 resulted in the identification of aminopterin, and thymidine Several hyper-phosphorylated proteins associated with the HPLC high pressure liquid chromatography inactive SHP-1 and/or SHP-2 (Zhao, Z., et al. (1995).J. Biol. ITIM immunoreceptor tyrosine-based inhibitory motif Chem. 270: 11765-17769; Su, L., et al. (1996).J. Biol. Chem. kDa kilodalton(s) 2.71:10385-10390. KR an ITIM-containing hematopoietic cell protein 40 KLH keyhole limpet hemocyanin Although a number of putative substrates of SHP-2 have LAIR an ITIM-containing hematopoietic cell protein Myr myristoylation been identified, little is known at the molecular level about PCR polymerase chain reaction the signaling mechanisms of SHP-2. This lack of knowledge PDGF platelet-derived growth factor represents a Serious deficiency in the art in View of the PTK protein tyrosine kinase effects of SHP-2 as described above.
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