Endocrinology, Vol 136, 5493-5503, Copyright © 1995 by Endocrine Society

ARTICLES

Inactivation of activin-dependent transcription by kinase-deficient activin receptors

K Tsuchida, JM Vaughan, E Wiater, D Gaddy-Kurten and WW Vale
Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

Activin, a member of the transforming growth factor-beta superfamily, binds to two classes of cell surface receptors. These receptors, designated type I and type II, are structurally related members of transmembrane serine kinase superfamily. Antibodies specific for either type I or type II activin receptor can coprecipitate complexes containing both affinity-labeled receptors from activin-responsive cells. Two type I receptors show cell-specific expression and associate with the ligand-binding, type II receptors. To investigate the roles of the cytoplasmic receptor domains in signaling through a heteromeric ligand receptor complex, we have made kinase-deficient activin receptors and correlated their losses in kinase activity with inhibitory effects on an activin-dependent transcriptional response in activin-responsive cell lines. Wild-type activin type II receptors phosphorylate activin type I receptors in transfected COS cells. In contrast, kinase-deficient activin type II receptors fail to phosphorylate type I receptors in transfected COS cells and act as dominant negative mutants to block activin-induced transcriptional activity in both Chinese hamster ovary and K562 (human erythroleukemia) cells. Kinase-deficient activin type IB receptors also block activin- induced transcriptional activity in both Chinese hamster ovary and K562 cells, whereas kinase-deficient activin type I receptors have no effect in either cell line. These results indicate that kinase activities of both type II and type I receptors are required for activin signaling, and that the two type I receptors, which are expressed in a tissue- specific manner, are functionally distinct.

This article has been cited by other articles:

				M.C. Ferreira, C.A. Witz, L.S. Hammes, N. Kirma, F. Petraglia, R.S. Schenken, and F.M. Reis Activin A increases invasiveness of endometrial cells in an in vitro model of human peritoneum Mol. Hum. Reprod., May 1, 2008; 14(5): 301 - 307. [Abstract] [Full Text] [PDF]

				J. A. Kelber, G. Shani, E. C. Booker, W. W. Vale, and P. C. Gray Cripto Is a Noncompetitive Activin Antagonist That Forms Analogous Signaling Complexes with Activin and Nodal J. Biol. Chem., February 22, 2008; 283(8): 4490 - 4500. [Abstract] [Full Text] [PDF]

				T. M Lovell, S. L Al-Musawi, R. T Gladwell, and P. G Knight Gonadotrophins modulate hormone secretion and steady-state mRNA levels for activin receptors (type I, IIA, IIB) and inhibin co-receptor (betaglycan) in granulosa and theca cells from chicken prehierarchical and preovulatory follicles Reproduction, June 1, 2007; 133(6): 1159 - 1168. [Abstract] [Full Text] [PDF]

				T Yamaguchi, A Kurisaki, N Yamakawa, K Minakuchi, and H Sugino FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor. J. Mol. Endocrinol., June 1, 2006; 36(3): 569 - 579. [Abstract] [Full Text] [PDF]

				Z H Liu, K Tsuchida, T Matsuzaki, Y L Bao, A Kurisaki, and H Sugino Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling. J. Endocrinol., May 1, 2006; 189(2): 409 - 421. [Abstract] [Full Text] [PDF]

				T M Lovell, P G Knight, and R T Gladwell Differential expression of mRNAs encoding the putative inhibin co-receptor (betaglycan) and activin type-I and type-II receptors in preovulatory and prehierarchical follicles of the laying hen ovary J. Endocrinol., February 1, 2006; 188(2): 241 - 249. [Abstract] [Full Text] [PDF]

				T M Lovell, P G Knight, and R T Gladwell Variation in pituitary expression of mRNAs encoding the putative inhibin co-receptor (betaglycan) and type-I and type-II activin receptors during the chicken ovulatory cycle J. Endocrinol., September 1, 2005; 186(3): 447 - 455. [Abstract] [Full Text] [PDF]

				C. Bamberger, A. Scharer, M. Antsiferova, B. Tychsen, S. Pankow, M. Muller, T. Rulicke, R. Paus, and S. Werner Activin Controls Skin Morphogenesis and Wound Repair Predominantly via Stromal Cells and in a Concentration-Dependent Manner via Keratinocytes Am. J. Pathol., September 1, 2005; 167(3): 733 - 747. [Abstract] [Full Text] [PDF]

				C. A. Harrison, P. C. Gray, S. C. Koerber, W. Fischer, and W. Vale Identification of a Functional Binding Site for Activin on the Type I Receptor ALK4 J. Biol. Chem., May 30, 2003; 278(23): 21129 - 21135. [Abstract] [Full Text] [PDF]

				P. C. Gray, C. A. Harrison, and W. Vale Cripto forms a complex with activin and type II activin receptors and can block activin signaling PNAS, April 29, 2003; 100(9): 5193 - 5198. [Abstract] [Full Text] [PDF]

				D. C. Danila, X. Zhang, Y. Zhou, J. N. S. Haidar, and A. Klibanski Overexpression of Wild-Type Activin Receptor Alk4-1 Restores Activin Antiproliferative Effects in Human Pituitary Tumor Cells J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4741 - 4746. [Abstract] [Full Text] [PDF]

				C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]

				T. Matsuzaki, S. Hanai, H. Kishi, Z. Liu, Y. Bao, A. Kikuchi, K. Tsuchida, and H. Sugino Regulation of Endocytosis of Activin Type II Receptors by a Novel PDZ Protein through Ral/Ral-binding Protein 1-dependent Pathway J. Biol. Chem., May 17, 2002; 277(21): 19008 - 19018. [Abstract] [Full Text] [PDF]

				L. Messika-Zeitoun, L. Gouedard, C. Belville, M. Dutertre, L. Lins, S. Imbeaud, I. A. Hughes, J.-Y. Picard, N. Josso, and N. di Clemente Autosomal Recessive Segregation of a Truncating Mutation of Anti-Mullerian Type II Receptor in a Family Affected by the Persistent Mullerian Duct Syndrome Contrasts with Its Dominant Negative Activity in Vitro J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4390 - 4397. [Abstract] [Full Text] [PDF]

				S. C. Chapman and T. K. Woodruff Modulation of Activin Signal Transduction by Inhibin B and Inhibin-Binding Protein (InhBP) Mol. Endocrinol., April 1, 2001; 15(4): 668 - 679. [Abstract] [Full Text]

				Y. Zhou, H. Sun, D. C. Danila, S. R. Johnson, D. P. Sigai, X. Zhang, and A. Klibanski Truncated Activin Type I Receptor Alk4 Isoforms Are Dominant Negative Receptors Inhibiting Activin Signaling Mol. Endocrinol., December 1, 2000; 14(12): 2066 - 2075. [Abstract] [Full Text]

				K. Kitamura, S.-i. Aota, R. Sakamoto, S.-I. Yoshikawa, and K. Okazaki Smad7 selectively interferes with different pathways of activin signaling and inhibits erythroid leukemia cell differentiation Blood, June 1, 2000; 95(11): 3371 - 3379. [Abstract] [Full Text] [PDF]

				D. C. Danila, X. Zhang, Y. Zhou, G. R. Dickersin, J. A. Fletcher, E. T. Hedley-Whyte, M. K. Selig, S. R. Johnson, and A. Klibanski A Human Pituitary Tumor-Derived Folliculostellate Cell Line J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1180 - 1187. [Abstract] [Full Text]

				H. Shoji, K. Tsuchida, H. Kishi, N. Yamakawa, T. Matsuzaki, Z. Liu, T. Nakamura, and H. Sugino Identification and Characterization of a PDZ Protein That Interacts with Activin Type II Receptors J. Biol. Chem., February 25, 2000; 275(8): 5485 - 5492. [Abstract] [Full Text] [PDF]

				P. C. Gray, J. Greenwald, A. L. Blount, K. S. Kunitake, C. J. Donaldson, S. Choe, and W. Vale Identification of a Binding Site on the Type II Activin Receptor for Activin and Inhibin J. Biol. Chem., February 4, 2000; 275(5): 3206 - 3212. [Abstract] [Full Text] [PDF]

				A. Lux, L. Attisano, and D. A. Marchuk Assignment of Transforming Growth Factor beta 1 and beta 3 and a Third New Ligand to the Type I Receptor ALK-1 J. Biol. Chem., April 9, 1999; 274(15): 9984 - 9992. [Abstract] [Full Text] [PDF]

				C. J. Donaldson, J. M. Vaughan, A. Z. Corrigan, W. H. Fischer, and W. W. Vale Activin and Inhibin Binding to the Soluble Extracellular Domain of Activin Receptor II Endocrinology, April 1, 1999; 140(4): 1760 - 1766. [Abstract] [Full Text]

				D. Chen, X. Ji, M.A. Harris, J.Q. Feng, G. Karsenty, A.J. Celeste, V. Rosen, G.R. Mundy, and S.E. Harris Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages J. Cell Biol., July 13, 1998; 142(1): 295 - 305. [Abstract] [Full Text] [PDF]

				Z. Gu, M. Nomura, B. B. Simpson, H. Lei, A. Feijen, J. van den Eijnden-van Raaij, P. K. Donahoe, and E. Li The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse Genes & Dev., March 15, 1998; 12(6): 844 - 857. [Abstract] [Full Text]

				N. Di Simone, H. A. Hall, C. Welt, and A. L. Schneyer Activin Regulates {beta}A-Subunit and Activin Receptor Messenger Ribonucleic Acid and Cellular Proliferation in Activin-Responsive Testicular Tumor Cells Endocrinology, March 1, 1998; 139(3): 1147 - 1155. [Abstract] [Full Text] [PDF]

				U. Persson, S. Souchelnytskyi, P. Franzen, K. Miyazono, P. ten Dijke, and C.-H. Heldin Transforming Growth Factor (TGF-beta )-specific Signaling by Chimeric TGF-beta Type II Receptor with Intracellular Domain of Activin Type IIB Receptor J. Biol. Chem., August 22, 1997; 272(34): 21187 - 21194. [Abstract] [Full Text] [PDF]

				J. W. M. Martens, J. P. de Winter, M. A. Timmerman, A. McLuskey, R. H. N. van Schaik, A. P. N. Themmen, and F. H. de Jong Inhibin Interferes with Activin Signaling at the Level of the Activin Receptor Complex in Chinese Hamster Ovary Cells Endocrinology, July 1, 1997; 138(7): 2928 - 2936. [Abstract] [Full Text] [PDF]

				K. Tsuchida, K. Y. Arai, Y. Kuramoto, N. Yamakawa, Y. Hasegawa, and H. Sugino Identification and Characterization of a Novel Follistatin-like Protein as a Binding Protein for the TGF-beta Family J. Biol. Chem., December 22, 2000; 275(52): 40788 - 40796. [Abstract] [Full Text] [PDF]