(updated 02/03)

CURRICULUM VITAE

NAME: JOSEPH ANDERS BEAVO, JR.

WORK ADDRESS:

Dept. of Pharmacology

Box 357280 Seattle, WA 98l17

University of Washington

Seattle, WA 98l95-7280

Phone (206) 543-4006 (wk) 206-789-8001 (hm)

FAX (206) 685-3822 email <beavo@u.washington.edu>

EDUCATION:

Stetson University, Deland, FL l96l-65, B.S. (Chemistry-Biology)

Vanderbilt University, Nashville, TN l965-70, Ph.D. (Physiology)

Major Professors: Drs. E. W. Sutherland & J. G. Hardman

University of California, Davis, CA l970-74, Postdoctoral Training

Department of Biological Chemistry, Director: Dr. Edwin G. Krebs

ACADEMIC APPOINTMENTS:

1986-present Professor, Department of Pharmacology

University of Washington

l977-1986 Asst. & Assoc. Professor, Department of Pharmacology

University of Washington

l974-l977 Adjunct Assistant Professor, Dept. of Biological Chemistry

University of California, Davis

NATIONAL MEMBERSHIPS, RESPONSIBILITIES & AWARDS:

1976-1981 Established Investigator, American Heart Assoc.

1980- American Society of Pharm. & Exp. Therapeutics (ASPET)

1979-1998 NIH, Physiological Chemistry, Biochemistry, Endocrinology, and

Pharmacology Ad Hoc Study Section Member

1984-1986 American Heart Association Study Section Member

1984-1987 Editorial Board, Molec. & Cell. Endocrinology

1986-1990 Associate Editor, Molecular Pharmacology

1989-1994 Editorial Board, J. Biol. Chem.

1995-2000 Editorial Board, Pharmacological Reviews

1993-1999 Program Committee, ASPET

1996- Member National Academy of Sciences, Editorial Board PNAS ('99 - present)

2000- Councilor, ASPET

STUDENTS TRAINED

PAST TRAINEES: PREDOCTORAL: CURRENT POSITION

Dr. Stuart Builder '76-78 Ph.D. Sr. Scientist, Genentech, Inc.

Dr. R. Scott Hansen '77-84 Ph.D. Res Asst Prof. Dept. of Med

Genetics, U. of Washington

Dr. Timothy Martins '79-84 Ph.D. Staff Scientist, ICOS Inc.

Bothell, WA

Dr. Scott Harrison '81-86 Ph.D. Staff Scientist at Genetic Systems

Andover, MA

Dr. Peter Gillespie '83-88 Ph.D. Assoc Prof., Dept Neurosci. Oregon HSU

Dr. Jeffrey Novak '84-90 Ph.D. Postdoctoral Fellow, G Nepom, U of Wash.

Dr. Ron MacFarland '84-90 Ph.D. Research Scientist, Sugen, Inc.

Dr. Jeri Beltman '86-93 Ph.D. Postdoctoral Fellow, S.Cook, ONYX

Dr. Timothy Bloom '88-96 Ph.D. Postdoctoral Fellow, Campbell University

Dr. Chen Yan '92-96 Ph.D. Res Asst Prof, Rochester.

Dr. Stephanie Florio '88-96 Ph.D. Research Scientist, ICOS Inc.

Dr. Dawn Julifs '88-97 Ph.D. Postdoctoral Fellow, Parke Davis.

Dr. Scott Soderling '94-99 Ph.D. Post Doctoral Fellow,Vollum Institute

Dr. Linsong Li '96-99 Ph.D. Professor, Bejing University

Dr. Terry Cook '95-01 Ph.D. Immunex

PAST TRAINEES: POSTDOCTORAL: CURRENT POSITION

Dr. Marc C. Mumby '79-83 Ph.D. Prof. of Pharmacology

Univ. of Texas, Dallas

Dr. Richard Hurwitz '80-84 M.D. Assoc. Prof. Medicine

Baylor University

Dr. Norbert Beier '84-86 Ph.D. Group Leader, Merck Inc.

Darmstadt, FDG

Dr. Colin Macphee '83-86 Ph.D. Senior Scientist

Smith/Kline/French, UK

Dr. David Reifsnyder '83-88 Ph.D. Staff Scientist,

Chiron, Inc. San Francisco

Dr. Harry Charbonneau '85-92 Ph.D. Assoc. Prof. of Biochemistry,

Purdue Univ.

Dr. Stephen Stroop '86-89 Ph.D. Staff Scientist,

ZymoGenetics, Seattle, WA

Dr. Vince Florio '90-92 Ph.D. Staff Scientist, ICOS, Inc

Bothell, WA

Dr. Rabi Prusti '88-92 Ph.D. Research Scientist,

Melville Biologics, Inc

Dr. J. Kelley Bentley '90-94 Ph.D. Res Asst. Prof., Univ. of Michigan

Ann Arbor, MI

Dr. Josep V. Planas '95-96 Ph.D. Res. Asst. Prof. Univ. de Barcelona,

Barcelona, Spain

Fiona Burns, '94-96 Ph.D. Res. Scientist, Biosource Intl.

Wm. Sonnenburg, '87-99 Ph.D. Private Business

Alan Zhao '94-99 Ph.D. Asst. Prof., U. of Pittsburg

Joanna Hetman, ë98-00 MD University of Warsaw

Natalie Glavas, '97-02 Ph.D. ACLARA Biosciences Inc.

(sabbatical )

Dr. Jerry Reek '84 Ph.D. Professor, Kansas State U.

Dr. Bulent Mutus '89 Ph.D. Professor, U. of Windsor

Dr. Rick Cote '96 Ph.D. Assoc. Prof., U. of New Hampshire

Dr. Ana Rascon '99 Ph.D. Assoc. Prof., U. of Caracas

CURRENT TRAINEES PREDOCTORAL FUNDING SOURCE

Daming Huang '98- Research Grant

Albert Wu '99 Poncin Fellowship

James Surapisitchat '01 NIH Training grant

Sunil Laxman '02 Research Grant

CURRENT TRAINEES POSTDOCTORAL FUNDING SOURCE

Sergei Rybalkin, Ph.D. '92- Research Grant.

Sergio Martinez, Ph.D. '95- Research Grant

Jennifer Glick, Ph.D. '98- Research Grant

Daniella Giordano, Ph.D. '99- Research Grant

Valeria Vasta, PhD '99- Research Grant

Andrew Bender '01- Research Grant

BIBLIOGRAPHY

Thesis: Cyclic GMP and Cyclic AMP Hydrolysis by Beef and Rat Tissues

1. Beavo, J. A., Hardman, J. G., and Sutherland, E. W. (l970) Hydrolysis of Cyclic Guanosine and Adenosine-3',5'-Monophosphates by Rat and Bovine Tisssues. J. Biol. Chem. 245:5649-5655.
2. Beavo, J. A., Rogers, N. L., Crofford, O. B., Hardman, J. G., Sutherland, E. W. and Newman, E. V. (l970) Effects of Xanthine Derivatives on Lipolysis and on Adenosine-3',5'-Monophosphate Phosphodiesterase Activity. Mol. Pharmacol. 6:597-603.
3. Beavo, J. A., Rogers, N.L., Crofford, O. B., Baird, C. E., Hardman, J. G., Sutherland, E. W. and Newman, E. V. (l97l) Effects of Phosphodiesterase Inhibitors on Cyclic AMP Levels and on Lipolysis. Ann. N.Y. Acad. Sci. 185:l29-l36.
4. Beavo, J. A., Hardman, J. G. and Sutherland, E. W. (l97l) Stimulation of Adenosine-3',5'-Monophosphate Hydrolysis by Guanosine 3',5'-Monophosphate. J. Biol. Chem. 246:384l-3846.
5. Hardman, J. G., Beavo, J. A., Gray, J. P., Chrisman, T. D., Patterson,W. D. and Sutherland, E. W. (l97l) Formation and Metabolism of Cyclic GMP. Ann. N.Y. Acad. Sci. 185:27.
6. Krebs, E. G., Beavo, J. A., Brostrom, C. O., Corbin, J. D., Hayakawa, T. and Walsh, D. A. (l97l) Mechanism of Action of Cyclic AMP in the Activation of Phosphorylase Kinase. In: International Symposium on Metabolic Interconversion of Enzymes, Rottach-Egern, West Germany, October, Springer-Verlag, Berlin, Heidelberg and New York, pp. ll3-ll7.
7. Beavo, J. A., Bechtel, P. G. and Krebs, E. G. (l975) Preparation of Homogeneous c AMP-Dependent Protein Kinase and its Subunits from Rabbit Skeletal Muscle. In: Methods in Enzymology, 38C, Academic Press, New York, pp. 299-308.
8. Krebs, E. G., Beavo, J. A., Bechtel, P. J., England, P. J., Huang, T. S. and Stull, J. T. (l974) Cyclic AMP and Protein Phosphorylation Reactions in Muscle. In: Exploratory Concepts in Muscle, Excerpta Medica, Amsterdam, pp. 43l-448.
9. Beavo, J. A., Bechtel, P. J. and Krebs, E. G. (l974) Activation of Protein Kinase by Physiological Concentration of Cyclic AMP. Proc. Nat. Acad. Sci. 71:3580-3583.
10. Dills, W. L., Beavo, J. A., Bechtel, P. J. and Krebs, E. G. (l975) Purification of Rabbit Skeletal Muscle Protein Kinase Regulatory Subunit Using Cyclic Adenosine-3,5'-Monophosphate Affinity Chromatography. Biochem. Biophys. Res. Comm. 62:70-77.
11. Beavo, J. A., Bechtel, P. J., Krebs, E. G. (l975) Mechanisms of Control cAMP Dependent Protein Kinase from Skeletal Muscle. Advances in Cyclic Nucleotide Research 5:24l-25l.
12. Shizuta, Y., Beavo, J. A., Bechtel, P. J., Hofmann, F. and Krebs, E. G. (l975) Reversibility of Adenosine 3',5'-Monophosphate-Dependent Protein Kinase Reactions. J. Biol. Chem. 250:689l-6896.
13. Hofmann, F., Beavo, J. A., Bechtel, P. J. and Krebs, E. G. (l975) Comparison of Adenosine-3',5'-Monophosphate-Dependent Protein Kinases from Rabbit Skeletal and Bovine Heart Muscle. J. Biol. Chem. 250:7795-780l.
14. Dills, W. L., Beavo, J. A., Bechtel, P. J., Myers, K. R., Sakai, L. J. and Krebs, E. G. (l976) Binding of Adenosine 3',5'-Monophosphate-Dependent Protein Kinase Regulatory Subunit to Immobilized Cyclic Nucleotide Derivatives. Biochemistry 15:3724-373l.
15. Bechtel, P. J., Beavo, J. A. and Krebs, E. G. (l977) Purification and Characterization of the Catalytic Subunit of Skeletal Muscle Adenosine 3',5'-Monophosphate-Dependent Protein Kinase. J. Biol. Chem. 252:2691-2697.
16. Steiner, A. L., Koide, Y., Earp, H. S., Bechtel, P. J. and Beavo, J. A. (l978) Compartmentalization of Cyclic Nucleotides and Cyclic AMP-Dependent Protein Kinases in Rat Liver: Immunocytochemical Demonstration. Adv. in Cylic Nuc. Res. 9:69l-705.
17. Steiner, A. L., Koide, Y., Spruill, W. A. and Beavo, J. A. (l978) The Distribution of Cyclic Nucleotides and Their Protein Kinases in Tissues: An Immunocytochemical Approach. Adv. Pharm. and Exp. Ther. 3:207-2l9.
18. Dills, W. L., Goodwin, C. O., Lincoln, T. M., Beavo, J. A. Bechtel, P. J., Corbin, J. D. and Krebs, E. G. (l978) Purification of Cyclic Nucleotide Receptors by Cyclic Nucleotide Affinity Chromatography. Adv. Cyclic Nucleotide Res. 10:199-218.
19. Krebs, E. G. and Beavo, J. A. (l979) Phosphorylation-Dephosphorylation of Enzymes. Ann. Rev. Biochem. 48:923-959.
20. Kapoor, C. L., Beavo, J. A. and Steiner, A. L. (l979) Radioimmunoassay of the Regulatory Subunit of Type I cAMP-dependent protein kinase. J. Biol. Chem. 254:l2427-32.
21. Builder, S. E., Beavo, J.A. and Krebs, E. G. (l980) Stoichiometry of cAMP and l,N6-Etheno-cAMP Binding to Protein Kinase. J. Biol. Chem. 255:2350-54.
22. Builder, S. E., Beavo, J. A. and Krebs, E. G. (l980) The Mechanism of Activation of Bovine Skeletal Muscle Protein Kinase by Adenosine 3',5'-Monophosphate. J. Biol. Chem. 255:35l4-l9 .
23. Mumby, M. and Beavo, J. A. (l980) Production and Characterization of Monoclonal Antibodies to Type II Regulatory Subunit of Cyclic AMP-Dependent Protein Kinase. Proc. W. Pharmacol. Soc. 23:369-73.
24. Browne, C. L., Lockwood, A. H., Su, J., Beavo, J. A., and Steiner, A. L. (1980) Immunofluorescent Localization of Cyclic Nucleotide-dependent Protein Kinases on the Mitotic Apparatus of Cultured Cells. J. Cell Biol. 87:336-45.
25. Beavo, J. A., and Hansen, R. S. (1981) Enzyme Purification Utilizing Conformation Specific Monoclonal Antibodies in Monoclonal Antibodies in Endocrine Research, Fellows and Ersenbarth, Eds. Raven Press N.Y., 157-166.
26. Beavo, J. A. and Mumby, M. C. (1981) cAMP Dependent phosphorylation. Handbook of Pharmacology. Chapter 11, Springer-Verlag, Heidelberg, 363-389.
27. Doherty, P., Tsao, J., Schimmer, B. P., Mumby, M. and Beavo, J. A. (1981) cAMP-dependent protein kinase and regulation of adreno-cortical functions - a genetic evaluation. Cold Spring Harbor Symposium -Protein Phosphorylation. 8:211-226.
28. Builder, S. E., Beavo, J. A. and Krebs, E. G. (1981) The Mechanismn of Activation and Inactivation of cAMP Dependent Protein Kinase: Several Lines of Evidence. Cold Spring Harbor Symposium - Protein Phosphorylation. 8:33-44.
29. Mumby, M. and Beavo, J. A. (1981) Unique Properties of Monoclonal Antibodies as Probes of the Structure, Function, and Regulations of Protein Kinases. Cold Spring Harbor Symposium - Protein Phosphorylation. 8:105-124.
30. Kapoor, C. L., Beavo, J. A. and Steiner, A. L. (1981) Radioimmunoassay of the Regulatory Subunit of Type I cAMP-Dependent Protein Kinase. Methods in Enzymology- Immunochemical Techniques. H.V. Vunakis and J.J.LaGone, Ed. Academic Press, NY, NY.
31. Cumming, R., Koide, Y., Krigman, M. R., Beavo, J. A., and Steiner, A. L. (1981) Immunofluorescent localization of regulatory and catalytic subunits of cAMP- dependent protein Kinase in neuronal and glial cell types of the central nervous system. Neuroscience 6:953-61.
32. Spruill, W. A., Koide, Y., Huang, H. L., Levine, S. N., Ong, S. H., Steiner, A. L., and Beavo, J. A. (1981) Immunocytochemical Localization of Cyclic Guanosine Monophosphate-dependent Protein Kinase in Endocrine Tissues. Endocrinology 109:2239-48.
33. Koide, Y., Beavo, J. A., Kapoor, C. L., Spruill, W. A., Huang, H. L., Levine, S. N., Ong, S. L., Bechtel, P. J., Yount, W. J., and Steiner, A. L. (1981) Hormonal Effects on the Immunocytochemical Location of 3'5' Cyclic Adenosine Monophosphate-dependent Protein Kinase in Rat Tissues. Endocrinology 109:2226-38.
34. Martins, T. J., Mumby, M. C., and Beavo, J. A. (1982) Purification and Characterization of a Cyclic GMP Stimulated Cyclic Nucleotide Phosphodiesterase from Bovine Tissues. J. Biol. Chem. 257:1973-1979.
35. Hansen, R. S. and Beavo, J. A. (1982) Purification of Two Calcium/calmodulin dependent Forms of Cyclic Nucleotide Phosphodiesterase Using Conformation-Specific Monoclonal Antibody Chromatography. PNAS 79:2788-92.
36. Doherty, P. J., Tsao, J., Schimmer, B. P., Mumby, M. C., and Beavo, J. A. (1982) Alteration of the Regulatory Subunit of Type 1 cAMP-dependent Protein Kinase in Mutant Y-1 Adrenal Cells Resistant to 8-Bromoadenosine 3':5'-Monophosphate. J. Biol. Chem. 257:5877-83.
37. Beavo, J. A., Hansen, R. S., Harrison, S. A., Hurwitz, R. L., Martins, T. J. and Mumby, M. C. (1982) Identification and Properties of Cyclic Nucleotide Phosphodiesterases. Mol. Cell Endocrinol. 28:387-410.
38. Mumby, M. C., Martins, T. J., Chang, M. L., and Beavo, J. A. (1982) Identification of cGMP-stimulated Cyclic Nucleotide Phosphodiesterase in Lung Tissue with Monoclonal Antibodies. J. Biol. Chem. 257:13283-13290.
39. Weldon, S. L., Mumby, M. C., Beavo, J. A., and Taylor, S. S. (1983) Monoclonal Antibodies as Structural Probes of Surface Residues in the Regulatory Subunit of cAMP-dependent Protein Kinase II from Porcine Heart. J. Biol. Chem. 258:1129-1135.
40. Hurwitz, R. L., Hansen, R. S., Harrison, S. A., Martins, T. J., Mumby, M. C., and Beavo, J. A. (1984) Immunologic Approaches to the Study of Cyclic Nucleotide Phosphodiesterases. Adv. Cyc. Nuc. Res. 16:89-106.
41. Hurwitz, R. L., Bunt-Milam, A. H., and Beavo, J. A. (1984) Immunologic Characterization of the Photoreceptor Outer Segment Cyclic GMP Phosphodiesterase. J. Biol. Chem. 259:8612-8618.
42. Hurwitz, R. L., and Beavo, J. A. (1984) Immunotitration analysis of the Rod Outer Segment Phosphodiesterase. Adv. Cyc. Nuc. Res. 17:239-248.
43. Hurwitz, R. L., Bunt-Milam, A. H., Chang, M. L., and Beavo, J. A. (1985) cGMP Phosphodiesterase in Rod and Cone Outer Segments of the Retina. J. Biol. Chem. 260:568-573.
44. Harrison, S. A., Chang, M. L., and Beavo, J. A. (1986) Differential Inhibition of Cardiac Cyclic Nucleotide Phosphodiesterase Isozymes by Cardiotonic Drugs. Circulation 73:(suppl III) 109-116.
45. Harrison, S. A., Reifsnyder, D. H., Gallis, B., Cadd, G. G., and Beavo, J. A. (1986) Isolation and Characterization of Bovine Cardiac Muscle cGMP-Inhibited Phosphodiesterase: A Receptor for New Cardiotonic Drugs. Mol. Phcol. 29:506-514.
46. Hansen, R. S. and Beavo, J. A. (1986) Differential Recognition of Calmodulin/Enzyme Complexes by a Conformation-Specific Anti-calmodulin Monoclonal Antibody. J. Biol. Chem. 261:14636-14645.
47. Macphee, C. H., Harrison, S. H., and Beavo, J. A. (1986) Immunological Identification of the Major Platelet Low Km cAMP Phosphodiesterase: A Probable Target for Anti-Thrombotic Agents. Proc. Nat. Acad. Sci. USA 83:6660-6663.
48. Charbonneau, H., Beier, N., Walsh, K. A., and Beavo, J. A. (1986) Identification of a Conserved Domain among Cyclic Nucleotide Phosphodiesterases from Diverse Species. Proc. Nat. Acad. Sci. USA 83:9308-9312.
49. Charbonneau, H., Novack, J. P., MacFarland, R. T., Walsh, K. A., and Beavo, J. A. (1987) Structure and function of calmodulin-dependent phosphodiesterase isozymes Calcium Binding Proteins and Health and Disease. Academic Press p505-517.
50. Harrison, S. A., Beier, N., Martins, T. J. and Beavo, J. A. (1988) Isolation and Comparison of Bovine Heart cGMP-Inhibited and cGMP-Stimulated Phosphodiesterases. Methods in Enzymology 159:685-701.
51. Hansen, R. S., Charbonneau, H. and Beavo, J. A. (1988) Purification of Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase by Monoclonal Antibody Affinity Chromatography. Methods in Enzymology 159:543-556.
52. Macphee, C. H., Reifsnyder, D. H., Moore, T. A., and Beavo, J. A. Intact cell and cell-free phosphorylation and concomitant activation of a low Km , cAMP phosphodiesterase found in human platelets. J. Cyc. Nuc. and Prot. Phos. Res. 11:487-496 (1988).
53. Macphee, C. H., Reifsnyder, D. H., Moore, T. A., Lerea, K. M., and Beavo, J. A. (1988) Phosphorylation results in activation of a cAMP phosphodiesterase in human platelets. J. Biol. Chem. 263:10353-10358.
54. Gillespie, P. G. and Beavo, J. A. (1988) Characterization of a Bovine Cone Photoreceptor Phosphodiesterase Purified by Cyclic GMP-sepharose Chromatography J. Biol. Chem . 263:8133-8141 .
55. Beavo, J. A. Multiple isozymes of cyclic nucleotide phosphodiesterase (1988) Adv. Cyc. Nuc. and Prot. Phos. Res. 22:1-38 .
56. Rapundolo, S. T., Lathrop, D. A., Harrison, S. A., Beavo, J. A., and Schwartz, A. (1988) Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212. Naunyn-Schmiedeberg's Arch Pharmacol. 338:692-698 .
57. Blumenthal, D. K., Charbonneau, H., Edelman, A. E., Hinds, T. R., Rosenberg, G. B., Storm, D. R., Vincenzi, F. F., Beavo, J. A., and Krebs, E. G. Synthetic peptides based on the calmodulin-binding domain of myosin light chain kinase inhibit activation of other calmodulin-dependent enzymes. Biochem. Biophys. Res. Comm. 156:860-865 (1988).
58. Gillespie, P .G. and Beavo, J. A. (1989) Cyclic GMP is tightly bound to bovine retinal rod phosphodiesterase. Proc. Nat. Acad. Sci. USA 86:4311-4315 (1989).
59. Gillespie, P. G., Prusti, R. K., Apel, E. D., and Beavo, J. A. A soluble form of bovine rod phosphodiesterase has a novel 15-kDa subunit. J. Biol. Chem. 264:12187-12193 (1989).
60. Stroop, S. D., Charbonneau, H., and Beavo, J. A. (1989) Direct photolabeling of allosteric and catalytic domains of the cGMP-stimulated cyclic nucleotide phosphodiesterase. J. Biol. Chem. 264:13718-13725.
61. Gillespie, P. G. and Beavo, J. A. (1989) Inhibition and stimulation of photoreceptor phosphodiesterases by dipyridamole and M&B 22,948. Mol. Pharm. 36:773-781.
62. Novack, J.P., Charbonneau, H., Blumenthal. D.K., Walsh, K.A., and Beavo, J.A. (1989) The domain structure of the calmodulin-dependent phosphodiesterase isozymes. Calcium Protein Signaling, Editors: H. Hidaka, E. Carafoli, A.R. Means, and T. Tanaka Plenum Publishing Company, pp. 387-395.
63. Charbonneau, H., Prusti, R. K., Trong, H. L., Sonnenburg, W. K., Mullaney, P. J., Walsh, K. A., and Beavo, J. A. (1990) Identification of a noncatalytic, cGMP-binding domain conserved in both the cGMP-stimulated and photoreceptor cyclic nucleotide phosphodiesterases. Proc. Nat. Acad. Sci. USA 87:288-292.
64. Beavo, J. A. and Reifsnyder, D. H. (1990) Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. TiPS 11:150-155.
65. Le Trong, H., Beier, N. L., Sonnenburg, W. K., Stroop, S. D., Walsh, K. A., Beavo, J. A. and Charbonneau, H. (1990) Amino acid sequence of the cyclic GMP-stimulated phosphodiesterase from bovine heart. Biochemistry 29:10280-10288.
66. Watson, E. L., Singh, J. C., McPhee, C., Beavo, J. A., and Jacobson, K. L. (1990) Evidence for a role of cGMP in cAMP metabolism in mouse parotid gland. Mol. Pharm. 38:547-553.
67. MacFarland, R. T. Stroop, S. D., and Beavo, J. A. (1990) Structural and Functional Characterization of Cyclic GMP-Stimulated Phosphodiesterases and Their Role in Intracellular Signal Transduction. In Purines in Cellular Signaling: Targets for New Drugs. K A. Jacobson, J.W. Daly, and V. Manganiello, Editors, Springer-Verlag New York
68. MacFarland, R.T., Zelus, B. D., and Beavo, J. A. (1991) High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. J. Biol. Chem. 266:136-142.
69. Charbonneau, H., Kumar, S., Novack, J. P., Blumenthal, D.K., Griffin, P.R., Shabanowitz, J. J., Hunt, D.F., Beavo, J.A., and Walsh, K.A. (1991) Evidence for domain organization within the 61 -kDa calmodulin-dependent cyclic nucleotide phosphodiesterase from bovine brain. Biochemistry 30:7931-7940.
70. Novack, J. P., Charbonneau, H., Walsh, K. A., and Beavo, J. A. (1991) Sequence comparison of the 63, 61, and 59 kDa calmodulin-dependent cyclic nucleotide phosphodiesterases. Biochemistry 30:7940-7947.
71. Sonnenburg, W. K., Mullaney, P. J., and Beavo, J. A. (1991) Molecular cloning of a cGMP-stimulated cyclic nucleotide phosphodiesterase cDNA: Identification and distribution of isozyme variants. J. Biol. Chem. 266:17655-17661.
72. Stroop, S. D. and Beavo, J. A. (1991) Structure and function studies of the cGMP-stimulated phosphodiesterase. J. Biol. Chem. 266:23802-23809.
73. Bentley, J. K. and Beavo, J. A. (1992) Regulation and function of cyclic nucleotides Cur Opin. in Cell. Biol. 4: 233-240.
74. Borisy, F. F., Ronnett, G. V., Cunningham, A. M., Julifs, D., Beavo, J.A., and Snyder, S. H. (1992) Calcium/calmodulin activated phosphodiesterase expressed in olfactory receptor neurons J. Neuroscience. 12:915-923.
75. Butt, E., Nolte, C. Schulz, S., Beltman, J., Beavo, J. A., Jastorff, B., and Walter, U. (1992) Analysis of the functional role of cGMP-dependent protein kinase in intact human platelets using a specific activator 8-pCPT-cGMP. Biochem. Pharmacol. 43:2591-2600.
76. Bentley, J. K., Kadlecek, A., Sonnenburg, W. K., Novack, J. P., Charbonneau, H., and Beavo, J. A. (1992) Molecular Cloning of cDNA Encoding a "63" kDa Calmodulin-stimulated Phosphodiesterase from Bovine Brain. J. Biol. Chem. 267: 18676-18682.
77. Sonnenburg, W. K., Segar, D., and Beavo, J. A. (1993) Molecular cloning of a cDNA encoding the "61 kDa" calmodulin-stimulated cyclic nucleotide phosphodiesterase: tissue-specific expression of structurally related isoforms. J. Biol. Chem. 268:645-652.
78. Hamilton, S. E., Prusti, R. K., Bentley, J. K., Beavo, J. A. and Hurley, J. B. (1993) Affinities of bovine photoreceptor cGMP phosphodiesterases for rod and cone inhibitory subunits. Febs Lett 318: 157-161.
79. Michaeli, T., Bloom, T. J., Martins, T., Loughney, K., Ferguson, K., Riggs, M., Rogers. L., Beavo, J. A., and Wigler, M. (1993). Isolation and characterization of a previously undetected human cAMP phosphodiesterase by complementation of cAMP phosphodiesterase-deficient Saccharomyces cerevisiae. J. Biol. Chem. 268:12925-12932.
80. Chan, S. C. , Reifsnyder, D., Beavo, J. A., and Hanifin, J. M. (1993) Immunochemical characterization of the distinct monocyte cyclic AMP-phosphodiesterase from patients with atopic dermatitis. J. Allergy Clin. Immunol. 91:1179-1188.
81. McAllister, L. M., Kadlecek, A. T., Sonnenburg, W. T., Seger, D., Francis, S. H., Thomas, M. K., Corbin, J. D. and Beavo, J. A. (1993) Isolation of a cDNA clone for the bovine lung cGMP-binding cGMP-specific phosphodiesterase. J. Biol. Chem. 268:22863-22873.
82. Beltman, J., Sonnenburg, W. K., and Beavo, J. A. (1993) The role of protein phosphorylation in the regulation of cyclic nucleotide phosphodiesterases. Molec. and Cell. Biochem. 127/128:239-253.
83. Sonnenburg, W. K. and Beavo, J. A. (1994) Cyclic GMP and regulation of cyclic nucleotide hydrolysis. Adv. in Pharmacol. 26:87-113.
84. Yan, C., Bentley, J. K., Sonnenburg, W. K. & Beavo, J. A. (1994) Differential expression of the 61 kDa and 63 kDa calmodulin-dependent phosphodiesterases in the mouse brain. J. Neuroscience 14:973-984.
85. Florio, V. A., Sonnenburg, W. K., Johnson, R., Kwak, K., Jensen, G. S., Charbonneau, H., Walsh, K. A., and Beavo, J. A. (1994) Phosphorylation of the "61 kDa" calmodulin-stimulated cyclic nucleotide phosphodiesterase at serine 120 reduces its affinity for calmodulin. Biochemistry 33:8948-8954.
86. Beavo, J. A., Conti, M., and Heaslip, R. J. (1994) Multiple cyclic nucleotide phosphodiesterases. Molec. Pharmacol. 46:399-405
87. Beltman, J., Becker, D. E., Butt, E., Jensen, G.S., Rybalkin S. D., Jastorff, B., and Beavo, J. A. (1995) Characterization of cyclic nucleotide phosphodiesterases with cyclic GMP analogs: topology of the catalytic domains. Mol. Pharmacol. 47:330-339.
88. Butt, E., Beltman, J., Becker, D. E., Jensen, G. S., Jastorff, B. and Beavo, J. A. (1995) Characterization of cyclic nucleotide phosphodisterases using cAMP analogs: the topology of the catalytic site and comparison to other cAMP-binding sites. Mol. Pharm. 47:340-347.
89. Beavo, J. A. (1995) cGMP inhibition of heart phosphodiesterase: is it clinically relevant? J. Clin. Investigation 95:445 .
90. Villacres, E. C. Wu, Z., Hua, W., Nielsen, M. D., Watters, J. J., Yan, C., Beavo, J. and Storm, D. R. (1995) Developmentaly Expressed Ca2+ -sensitive adenylyl cyclase activity is disrupted in the brains of type I adenylyl cyclase mutant mice. J. Biol. Chem. 270:14352-14357.
91. Beavo, J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiological Reviews 75:725-747.
92. Yan, C., Bentley, J. K., Zhao, A., Loughney, K., and Beavo, J. A. (1995) Molecular cloning and characterization of a novel, high affinity calmodulin-dependent cyclic nucleotide phosphodiesterase selectively expressed in olfactory neurons. PNAS 92:9677-9681
93. McAllister-Lucas, L.M., T.L. Haik, J.L. Colbran, W.K. Sonnenburg, D. Seger, J. A. Beavo, and J. D. Corbin (1995) An essential aspartic acid at each of two allostric cGMP binding sites of a cGMP-specific phosphodiesterase. J. Biol. Chem. 270:30671-30679.
94. Sonnenburg, W. K., Seger, D., Kwak, K. S., Huang, J., Charbonneau, H., Beavo, J. A. (1995) Identification of inhibitory and calmodulin-binding domains of the "59-kDa" and"61-kDa" calmodulin stimulated phosphodiesterases J. Biol. Chem. 270:30989-31000.
95. Loughney, K., Martins, T.J., Harris, E.A.S., Sadhu, K., Hicks, J.B., Sonnenburg, W.K., Beavo, J.A. and Ferguson, K. (1996) Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3',5' cyclic nucleotide phosphodiesterases: HSPDE1A and HSPDE1C. J. Biol. Chem. 271:796-806.
96. Bentley, J. K. and Beavo, J. A. (1996) Role of multiple isozymes in the regulation of cyclic nucleotide synthesis and degradation. Principles in Medical Biology. Cell Chemistry and Physiology: Part II. Edward Bittar and Neville Bittar Editors. JAI Press Greenwich, Inc., Greenwich, CT.p 77-121.
97. Burns, F., Zhao, A. Z., and Beavo, J. A. (1996) Cyclic nucleotide phosphodiesterases: gene complexity, regulation by phosphorylation and physiological implications. Adv. in Pharmacol. 36:29-48.
98. Florio, S. K., Prusti, R. K., and Beavo, J. A. (1996) Solubilization of membrane bound rod phosphodiesterase by the rod phosphodiesterase delta subunit: structure, localization and function of the delta subunit. J. Biol. Chem. 271:24036-24047.
99. Yan, C., Zhao, A., Bentley, J. K., and Beavo, J. A. (1996) The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue specific manner. J. Biol. Chem. 271:25699-25706.
100. Bloom, T. J. and Beavo, J.A. (1996) Identification and tissue specific expression of PDE7 phosphodiesterase splice variants. Proc. Nat. Acad. Sci. USA 93:14188-14192.
101. Rybalkin, S. D. and J. A. Beavo (1996). Multiplicity within cyclic nucleotide phosphodiesterases. Biochemical Society Transactions 24: 1005-1009.
102. Zhao, A. Z., H. Zhao, J. Teague, W. Fugimoto and J. A. Beavo (1997). Attenuation of insulin secretion by IGF-1 is mediated through activation of phosphodiesterase 3B (PDE3B). Proc. Nat Acad. Sci. USA 94:3223-3228.
103. Juilfs, D. W., Fulle, H. J., Zhao, A. Z., Houslay, M. D., Garbers, D. L., and Beavo, J. A. (1997) A subset of neurons that selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclase-D define a unique olfactory signal transduction pathway. Proc. Nat. Acad. Sci. USA 94:3388-3395.
104. Rosman, G. J., Martins, T. J., Sonnenburg, W. K., Beavo, J. A, Ferguson, K. and Loughney, K. (1997) Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase. Gene 191:89-95.
105. Yu, J., Wolda, S.L., Frazer, A.L.B., Florio, V.A., Martins, T.J., Snyder, P.B., Harris, E.A.S.,McDaw, K.N., Farrell, C.A., Steiner, B., Bentley, J.K., Beavo, J.A., Ferguson, K., Gelinas, R. (1997) Identification and characterization of a human calmodulin-stimulated phosphodiesterase PDE1B1 Cell. Signal. 9:519-529.
106. Zhao, A. Z., Yan, C., Sonnenburg, W. K., and Beavo, J. A. (1997) Recent advances in the study of Ca2+/CaM activated phosphodiesterases: expression and physiological functions. Signal Transduction in Health and Disease 31:237-251.
107. Rybalkin, S. D., Bornfeldt, K. E., Sonnenburg, W. K., Rybalkina, I. G., Kwak, K. S., Hansen, K., Krebs, E. G., and Beavo, J. A. (1997) Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J. Clin. Invest. 100:2611-2621.
108. Sonnenburg, W.K., Rybalkin, S.D., Bornfeldt, K.E. Kwak, K.S. Rybalkina, I.G. and Beavo, J.A. (1998) Identification , quantitation, and cellular localization of PDE1 calmodulin-stimulated cyclic nucleotide phosphodiesterases. Methods: A companion to methods in enzymology. 14:3-19.
109. Sonnenburg, W. K., G. A. Wayman, D. A. Storm and J. A. Beavo (1997). Cyclic nucleotide regulation by calmodulin. Calmodulin and signal transduction. San Diego, Academic Press. 237-286.
110. Soderling, S.H., Bayuga, S.J., and Beavo, J.A. (1998) Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J. Biol. Chem. 273:15553-15558.
111. Soderling, S.H. Bayuga, S.J., and Beavo, J.A. (1998) Cloning and characterization of a novel cAMP specific cyclic nucleotide phosphodiesterase. Proc. Nat. Acad. Sci. 95:8991-8996.
112. Hanson, K.A., Burns, F., Rybalkin, S.D., Wager-Miller, J., Beavo, J.A. and Clarke, W. R. (1998) Developmental changes in lung cGMP phosphodiesterase-5 activity, protein, and message. Am. J. Crit. Care Med. 158:279-288.
113. Li, N., Florio, S.K., Pettenati, M.J., Nagesh-Rao, P., Beavo, J.A., and Baehr, W. (1998) Characterization of human and mouse rod cGMP phosphodiesterase gamma subunit (PDE6) and chromosomal localization of the human gene. Genomics 49:76-82.
114. Zhao, A.Z., Bornfeldt, K.E., and Beavo, J.A. (1998) Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J. Clin. Invest. 102:869-873.
115. Wei, J, Zhao, A.Z., Chan, G.C., Baker, L.P., Impey, S, Beavo, J.A., and Storm, D. R. (1998) Phosphorylation and inhibition of olfactory adenylyl cyclase by CaM kinase II in neurons: a mechanism for attenuation of olfactory signals. Neuron 21:1-20.
116. Loughney, K, Hill, T.R., Florio, V.A.. Uhler, L., Rosman, G.J. Wolda, S.L., Jones, B.A., Howard, M.L., McAllister-Lucas, L.M., Sonnenburg, W.K., Francis, S.H., Corbin, J.D., Beavo, J.A., Ferguson, K. (1998) Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3í5í-cyclic nucleotide phosphodiesterase Gene 216:139-147.
117. Juilfs, D. M., Soderling, S., Burns, F., and Beavo, J.A. (1999) Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs). Reviews of Physiology Biochemistry and Pharmacology, 135:67-104 Springer Verlag.

118. Li, L, Yee, C., and Beavo, J.A. (1999) CD3 and CD28 dependent induction of PDE7 required for T cell activation. Science 283:848-851.

119. Mou, H., Grazio, H.J., Cook, T.A., Beavo, J.A., and Cote, R.H. (1999) cGMP binding to non catalytic sites on mammalian rod photoreceptor phosphodiesterase is regulated by binding of its g and d subunits. J. Biol. Chem. 274:18813-18820.

120. Soderling, S.H., Bayuga, S.J., and Beavo, J.A. (1999) Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc. Nat. Acad. Sci. USA 96:7071-7076.

121. Hetman J.M., Soderling S.H., Glavas N.A., Beavo J.A. (2000) Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase. Proc Natl Acad Sci U S A 97:472-476

122. Soderling, S.H. and Beavo, JA (2000) Regulation of cAMP and cGMP signaling: New Phosphodiesterases and New Functions. Cur. Opin. Cell Biol.12:174-179

123. Zhao, A.Z., Shinohara, M.M., Huang, D., Shimizu, M., Eldar-Finkleman, H. Krebs, E.G., Beavo, J.A. and Bornfeldt, K.E. (2000) Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J. Biol. Chem. 275:11348-11354

124. Fawcett, L., Baxendale, R., Stacey, P., McGrouther. C., Harrow, I., Soderling, S.H., Hetman, J.M., Beavo, J.A. and Phillips, S.C. (2000) Molecular cloning and characterization of a novel human phosphodiesterase gene family: PDE11A. Proc. Nat. Acad. Sci. USA 97:3702-7

125. Cook TA, and Beavo JA. (2000) Purification and assay of bovine type 6 photoreceptor phosphodiesterase and its subunits. Methods Enzymol. 315:597-616.

126. Sun Y, Li L, Lau F, Beavo JA, Clark EA.Infection of CD4⁺ memory T cells by HIV-1 requires expression of phosphodiesterase 4. J Immunol. 2000:1755-1761

127. Hetman, JM, Robas, N., Baxendale. R., Fidock, M., Phillips, S.C., Soderling, S.H., Beavo, J.A. Cloning and characterization of two novel splice variants of human phosphodiesterase 11A. Proc. Nat. Acad. Sci. 2000 Nov 7;97(23):12891-5.

128. Cook, TA, Ghomaschi, F, Gelb, MH, Florio, SK, and Beavo, JA. Binding of the Delta Subunit to Rod Phosphodiesterase Catalytic Subunits Requires Methylated, Prenylated C-termini of the Catalytic Subunits. Biochemistry. 2000 Nov 7;39(44):13516-23.

129. Cook, TA, Ghomaschi, F, Gelb, MH, Florio, SK, and Beavo, JA. (2001) The delta subunit of type 6 phosphodiesterase reduces light-induced cGMP hydrolysis in rod outer segments. J. Biol. Chem, Feb 16;276(7):5248-5255

130. Yan, C. Zhao, A.Z., Sonnenburg, W.K., and Beavo, J.A. (2001) Distinct spatial and temporal patterns of different Ca⁺⁺/calmodulin-stimulated phosphodiesterases in mouse testis. Biology of Reproduction 64:1746-1754

131. Shimizu-Albergine, M., Ippolito, D, and Beavo, JA. (2001) Down-regulation of fasting-induced CRE-mediated gene induction by leptin in neuropeptide Y neurons of the arcuate nucleus J. Neuro Sci, Feb 15;21(4):1238-1246

132. Glavas NA, Ostenson C, Schaefer JB, Vasta V, Beavo JA. (2001) T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 and 7A3. Proc Natl Acad Sci U S A May 22;98:6319-24

133. Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C. Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation 2001 Nov 6;104:2338-43

134. RascÛn, A., Soderling. SH. and Beavo, JA. Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4714-4719.

135. Rybalkin SD, Rybalkina I, Beavo JA, Bornfeldt KE. Cyclic nucleotide phosphodiesterase 1C promotes human arterial smooth muscle cell proliferation. Circ Res. 2002 Feb 8;90(2):151-7

136. Rybalkin SD, Rybalkina IG, Feil R, Hofmann F, Beavo JA. Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem. 2002 Feb 1;277(5):3310-7.

137. Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG, Beavo JA The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13260-5.

138 Rybalkin SD, Rybalkina IG, Shimizu-Albergine M, Tang XB, Beavo J PDE5 is converted to an activated state upon cGMP binding to the GAF A domain.EMBO J. 2003 Feb 3;22(3):469-78.

139 Beavo JA, Brunton LL. Cyclic nucleotide research -- still expanding after half a century. Nat Rev Mol Cell Biol. 2002 Sep;3(9):710-8.

140 Murradov KG, Boyd KK, Martinez SE, Beavo JA, Artemyev NO. The GAFa domains of rod cGMP-phosphodiesterase 6 determine the selectivity of the enzyme dimerization. J Biol Chem. 2003 Jan 16

Brief Summary of Research Program

Dr. Beavo's research group investigates the role of cyclic nucleotide phosphodiesterases (PDEs) in controlling the amplitude and duration of cyclic AMP and cyclic GMP signaling pathways. There are a large number of different isozyme families of PDEs that are differentially regulated by drugs and hormones. Many were first discovered and studied in this laboratory. Included among the agents that regulate PDEs are insulin, glucagon, EDRF and many neurotransmitters. Much of our recent work has been to determine the physiological reasons for the existence of so many isozymes and to understand mechanistically how they function. In order to understand the mechanisms by which different phosphodiesterases are regulated and influence cyclic AMP and cyclic GMP, several different general approaches have been and are being used. The first involves identification, expression or isolation of individual isozyme of phosphodiesterase present in different mammalian tissues. The structural, functional, and kinetic properties of the isolated isozymes are then characterized. A second and related approach has been to develop isozyme specific probes to each phosphodiesterase and utilize them to study localization, function and regulation in crude systems and in intact cells. These include monoclonal antibodies, antisense mRNAs, and various drugs. Finally, deletion and mutagenesis analysis, analysis of dominant negative mutants, and reconstitution studies with the expressed products is often used to determine function. More recently we have also initiated gene disruption studies as a mechanism of determining function. Taken together these approaches have yielded at least a partial understanding of the structure, regulation and function of these enzymes in the cell. Particular systems of current interest include the roles of PDEs in visual and olfactory signaling, exocytotic secretion, synaptic plasticity, pulmonary vascular function, inflammation, insulin secretion and leptin action. Very recently we have determined the crystal structure of one of the major regulatory domains of several of the PDEs and are working to understand how structure relates to function.