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Science 12 February 1999:
Vol. 283. no. 5404, pp. 990 - 993
DOI: 10.1126/science.283.5404.990
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Reports

Erythropoietin Receptor Activation by a Ligand-Induced Conformation Change

Ingrid Remy, 1 Ian A. Wilson, 2 Stephen W. Michnick 1*

Erythropoietin and other cytokine receptors are thought to be activated through hormone-induced dimerization and autophosphorylation of JAK kinases associated with the receptor intracellular domains. An in vivo protein fragment complementation assay was used to obtain evidence for an alternative mechanism in which unliganded erythropoietin receptor dimers exist in a conformation that prevents activation of JAK2 but then undergo a ligand-induced conformation change that allows JAK2 to be activated. These results are consistent with crystallographic evidence of distinct dimeric configurations for unliganded and ligand-bound forms of the erythropoietin receptor.

1 Département de Biochimie, Université de Montréal, Casier Postal 6128, succursale Centre-ville, Montréal, Québec, H3C 3J7, Canada.
2 Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
*   To whom correspondence should be addressed.

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F. K.-M. Chan, H. J. Chun, L. Zheng, R. M. Siegel, K. L. Bui, and M. J. Lenardo (2000)
Science 288, 2351-2354
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Growth Hormone (GH)-independent Dimerization of GH Receptor by a Leucine Zipper Results in Constitutive Activation.
S. N. Behncken, N. Billestrup, R. Brown, J. Amstrup, B. Conway-Campbell, and M. J. Waters (2000)
J. Biol. Chem. 275, 17000-17007
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Activation of Downstream Signals by the Long Form of the Leptin Receptor.
A. S. Banks, S. M. Davis, S. H. Bates, and M. G. Myers Jr. (2000)
J. Biol. Chem. 275, 14563-14572
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Protein-protein interactions define specificity in signal transduction.
T. Pawson and P. Nash (2000)
Genes & Dev. 14, 1027-1047
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Genuine Monovalent Ligands of TrkA Nerve Growth Factor Receptors Reveal a Novel Pharmacological Mechanism of Action.
S. Maliartchouk, T. Debeir, N. Beglova, A. C. Cuello, K. Gehring, and H. U. Saragovi (2000)
J. Biol. Chem. 275, 9946-9956
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Bone Morphogenetic Protein Receptor Complexes on the Surface of Live Cells: A New Oligomerization Mode for Serine/Threonine Kinase Receptors.
L. Gilboa, A. Nohe, T. Geissendörfer, W. Sebald, Y. I. Henis, and P. Knaus (2000)
Mol. Biol. Cell 11, 1023-1035
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Studies on the Interleukin-6-type Cytokine Signal Transducer gp130 Reveal a Novel Mechanism of Receptor Activation by Monoclonal Antibodies.
G. Muller-Newen, A. Kuster, J. Wijdenes, F. Schaper, and P. C. Heinrich (2000)
J. Biol. Chem. 275, 4579-4586
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A Designed Peptidomimetic Agonistic Ligand of TrkA Nerve Growth Factor Receptors.
S. Maliartchouk, Y. Feng, L. Ivanisevic, T. Debeir, A. C. Cuello, K. Burgess, and H. U. Saragovi (2000)
Mol. Pharmacol. 57, 385-391
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Kinetics of T-cell Receptor Binding by Bivalent HLA-DR{middle dot}Peptide Complexes That Activate Antigen-specific Human T-cells.
H. Appel, L. Gauthier, J. Pyrdol, and K. W. Wucherpfennig (2000)
J. Biol. Chem. 275, 312-321
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Monomeric Structure of the Human EphB2 Sterile alpha Motif Domain.
C. D. Thanos, S. Faham, K. E. Goodwill, D. Cascio, M. Phillips, and J. U. Bowie (1999)
J. Biol. Chem. 274, 37301-37306
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Functional Analysis of a Single Chain Chimeric alpha /beta -Granulocyte-Macrophage Colony-stimulating Factor Receptor. IMPORTANCE OF A GLUTAMATE RESIDUE IN THE TRANSMEMBRANE REGION.
S. Kafert, S. Luther, I. Boll, K. Wagner, A. Ganser, and M. Eder (1999)
J. Biol. Chem. 274, 33064-33071
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Determination of the Binding Site on the Extracellular Domain of Guanylyl Cyclase C to Heat-stable Enterotoxin.
M. Hasegawa, Y. Hidaka, Y. Matsumoto, T. Sanni, and Y. Shimonishi (1999)
J. Biol. Chem. 274, 31713-31718
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Extracellular Domain of the Transforming Growth Factor-beta Receptor Negatively Regulates Ligand-independent Receptor Activation.
H.-J. Zhu and A. M. Sizeland (1999)
J. Biol. Chem. 274, 29220-29227
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The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis.
D. A. Profant, C. J. Roberts, A. J. Koning, and R. L. Wright (1999)
Mol. Biol. Cell 10, 3409-3423
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