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Molecular Endocrinology 12 (2): 302-313
Copyright © 1998 by The Endocrine Society

Nuclear Receptor-Binding Sites of Coactivators Glucocorticoid Receptor Interacting Protein 1 (GRIP1) and Steroid Receptor Coactivator 1 (SRC-1): Multiple Motifs with Different Binding Specificities

Xiu Fen Ding1, Carol M. Anderson1, Han Ma, Heng Hong, Rosalie M. Uht, Peter J. Kushner1 and Michael R. Stallcup1

Departments of Pathology and of Biochemistry and Molecular Biology (X.F.D., H.M., H.H., M.R.S.) University of Southern California Los Angeles, California 90033
Metabolic Research Unit (C.M.A., R.M.U., P.J.K.) University of California San Francisco, California 94143

The activity of the AF-2 transcriptional activation function of nuclear receptors (NR) is mediated by the partially homologous transcriptional coactivators, glucocorticoid receptor interacting protein 1 (GRIP1)/transcriptional intermediary factor 2 (TIF2) and steroid receptor coactivator 1 (SRC-1). GRIP1 and SRC-1 bound nine different NRs and exhibited similar, but not identical, NR binding preferences. The most striking difference was seen with the androgen receptor, which bound well to GRIP1 but poorly to SRC-1. GRIP1 and SRC-1 contain three copies of the NR binding motif LXXLL (called an NR Box) in their central regions. Mutation of both NR Box II and NR Box III in GRIP1 almost completely eliminated functional and binding interactions with NRs, indicating that these two sites are crucial for most of GRIP1’s NR binding activity. Interactions of GRIP1 with the estrogen receptor were more strongly affected by mutations in NR Box II, whereas interactions with the androgen receptor and glucocorticoid receptor were more strongly affected by NR Box III mutations. One isoform of SRC-1 has an additional NR Box (NR Box IV) at its extreme C terminus with an NR-binding preference somewhat different from that of the central NR-binding domain of SRC-1. GRIP1 has no NR Box in its C-terminal region and therefore no C-terminal NR-binding function. In summary, GRIP1 and SRC-1 have overlapping NR-binding preferences, but specific NRs display both coactivator and NR Box preferences that may contribute to the specificity of hormonal responses.




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Mol. Cell. Biol., March 1, 2004; 24(5): 2103 - 2117.
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Mol. Endocrinol.Home page
L. Pascual-Le Tallec, O. Kirsh, M.-C. Lecomte, S. Viengchareun, M.-C. Zennaro, A. Dejean, and M. Lombes
Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 1 Interacts with the N-Terminal Domain of Mineralocorticoid Receptor and Represses Its Transcriptional Activity: Implication of Small Ubiquitin-Related Modifier 1 Modification
Mol. Endocrinol., December 1, 2003; 17(12): 2529 - 2542.
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J. Biol. Chem.Home page
K. Brown, Y. Chen, T. M. Underhill, J. S. Mymryk, and J. Torchia
The Coactivator p/CIP/SRC-3 Facilitates Retinoic Acid Receptor Signaling via Recruitment of GCN5
J. Biol. Chem., October 10, 2003; 278(41): 39402 - 39412.
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Nucleic Acids ResHome page
L. Ding, J. Yan, J. Zhu, H. Zhong, Q. Lu, Z. Wang, C. Huang, and Q. Ye
Ligand-independent activation of estrogen receptor {alpha} by XBP-1
Nucleic Acids Res., September 15, 2003; 31(18): 5266 - 5274.
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Cancer Res.Home page
K. Nishimura, H.-J. Ting, Y. Harada, T. Tokizane, N. Nonomura, H.-Y. Kang, H.-C. Chang, S. Yeh, H. Miyamoto, M. Shin, et al.
Modulation of Androgen Receptor Transactivation by Gelsolin: A Newly Identified Androgen Receptor Coregulator
Cancer Res., August 15, 2003; 63(16): 4888 - 4894.
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J. Biol. Chem.Home page
T. Fujita, Y. Kobayashi, O. Wada, Y. Tateishi, L. Kitada, Y. Yamamoto, H. Takashima, A. Murayama, T. Yano, T. Baba, et al.
Full Activation of Estrogen Receptor {alpha} Activation Function-1 Induces Proliferation of Breast Cancer Cells
J. Biol. Chem., July 11, 2003; 278(29): 26704 - 26714.
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Mol. Cell. Biol.Home page
X. Li, J. Wong, S. Y. Tsai, M.-J. Tsai, and B. W. O'Malley
Progesterone and Glucocorticoid Receptors Recruit Distinct Coactivator Complexes and Promote Distinct Patterns of Local Chromatin Modification
Mol. Cell. Biol., June 1, 2003; 23(11): 3763 - 3773.
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J. Biol. Chem.Home page
F. Liang, P. Webb, A. Marimuthu, S. Zhang, and D. G. Gardner
Triiodothyronine Increases Brain Natriuretic Peptide (BNP) Gene Transcription and Amplifies Endothelin-dependent BNP Gene Transcription and Hypertrophy in Neonatal Rat Ventricular Myocytes
J. Biol. Chem., April 18, 2003; 278(17): 15073 - 15083.
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Proc. Natl. Acad. Sci. USAHome page
C. J. Loy, K. S. Sim, and E. L. Yong
Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions
PNAS, April 15, 2003; 100(8): 4562 - 4567.
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Mol. Endocrinol.Home page
Y. Bai and V. Giguere
Isoform-Selective Interactions between Estrogen Receptors and Steroid Receptor Coactivators Promoted by Estradiol and ErbB-2 Signaling in Living Cells
Mol. Endocrinol., April 1, 2003; 17(4): 589 - 599.
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J. Biol. Chem.Home page
V. H. Coulthard, S. Matsuda, and D. M. Heery
An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220
J. Biol. Chem., March 21, 2003; 278(13): 10942 - 10951.
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Mol. Cell. Biol.Home page
B. He and E. M. Wilson
Electrostatic Modulation in Steroid Receptor Recruitment of LXXLL and FXXLF Motifs
Mol. Cell. Biol., March 15, 2003; 23(6): 2135 - 2150.
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Mol. Endocrinol.Home page
J. Liu, K. S. Knappenberger, H. Kack, G. Andersson, E. Nilsson, C. Dartsch, and C. W. Scott
A Homogeneous in Vitro Functional Assay for Estrogen Receptors: Coactivator Recruitment
Mol. Endocrinol., March 1, 2003; 17(3): 346 - 355.
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J. Biol. Chem.Home page
Y. Wu, W. W. Chin, Y. Wang, and T. P. Burris
Ligand and Coactivator Identity Determines the Requirement of the Charge Clamp for Coactivation of the Peroxisome Proliferator-activated Receptor gamma
J. Biol. Chem., February 28, 2003; 278(10): 8637 - 8644.
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Mol. Endocrinol.Home page
C. Teyssier, K. Belguise, F. Galtier, V. Cavailles, and D. Chalbos
Receptor-Interacting Protein 140 Binds c-Jun and Inhibits Estradiol-Induced Activator Protein-1 Activity by Reversing Glucocorticoid Receptor-Interacting Protein 1 Effect
Mol. Endocrinol., February 1, 2003; 17(2): 287 - 299.
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J. Biol. Chem.Home page
T. Kino and G. P. Chrousos
Tumor Necrosis Factor alpha Receptor- and Fas-associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators
J. Biol. Chem., January 24, 2003; 278(5): 3023 - 3029.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
I. Rogatsky, H. F. Luecke, D. C. Leitman, and K. R. Yamamoto
Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts
PNAS, December 24, 2002; 99(26): 16701 - 16706.
[Abstract] [Full Text] [PDF]


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V. Christiaens, C. L. Bevan, L. Callewaert, A. Haelens, G. Verrijdt, W. Rombauts, and F. Claessens
Characterization of the Two Coactivator-interacting Surfaces of the Androgen Receptor and Their Relative Role in Transcriptional Control*
J. Biol. Chem., December 13, 2002; 277(51): 49230 - 49237.
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J. Biol. Chem.Home page
Y. He, D. Szapary, and S. S. Simons Jr.
Modulation of Induction Properties of Glucocorticoid Receptor-Agonist and -Antagonist Complexes by Coactivators Involves Binding to Receptors but Is Independent of Ability of Coactivators to Augment Transactivation
J. Biol. Chem., December 13, 2002; 277(51): 49256 - 49266.
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J. Biol. Chem.Home page
M. A. Rao, H. Cheng, A. N. Quayle, H. Nishitani, C. C. Nelson, and P. S. Rennie
RanBPM, a Nuclear Protein That Interacts with and Regulates Transcriptional Activity of Androgen Receptor and Glucocorticoid Receptor
J. Biol. Chem., December 6, 2002; 277(50): 48020 - 48027.
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J. Biol. Chem.Home page
C. Teyssier, D. Chen, and M. R. Stallcup
Requirement for Multiple Domains of the Protein Arginine Methyltransferase CARM1 in Its Transcriptional Coactivator Function
J. Biol. Chem., November 22, 2002; 277(48): 46066 - 46072.
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J. Biol. Chem.Home page
M. E. Torres-Padilla, F. M. Sladek, and M. C. Weiss
Developmentally Regulated N-terminal Variants of the Nuclear Receptor Hepatocyte Nuclear Factor 4alpha Mediate Multiple Interactions through Coactivator and Corepressor-Histone Deacetylase Complexes
J. Biol. Chem., November 15, 2002; 277(47): 44677 - 44687.
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Mol. Endocrinol.Home page
T. Barkhem, L.-A. Haldosen, J.-A. Gustafsson, and S. Nilsson
Transcriptional Synergism on the pS2 Gene Promoter between a p160 Coactivator and Estrogen Receptor-{alpha} Depends on the Coactivator Subtype, the Type of Estrogen Response Element, and the Promoter Context
Mol. Endocrinol., November 1, 2002; 16(11): 2571 - 2581.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
C. M. Litterst and E. Pfitzner
An LXXLL Motif in the Transactivation Domain of STAT6 Mediates Recruitment of NCoA-1/SRC-1
J. Biol. Chem., September 20, 2002; 277(39): 36052 - 36060.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
S. Kaul, P. J. M. Murphy, J. Chen, L. Brown, W. B. Pratt, and S. S. Simons Jr.
Mutations at Positions 547-553 of Rat Glucocorticoid Receptors Reveal That hsp90 Binding Requires the Presence, but Not Defined Composition, of a Seven-amino Acid Sequence at the Amino Terminus of the Ligand Binding Domain
J. Biol. Chem., September 20, 2002; 277(39): 36223 - 36232.
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J. Biol. Chem.Home page
P. Delerive, W. W. Chin, and C. S. Suen
Identification of Reverbalpha as a Novel RORalpha Target Gene
J. Biol. Chem., September 13, 2002; 277(38): 35013 - 35018.
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J. Biol. Chem.Home page
N. Kotaja, U. Karvonen, O. A. Janne, and J. J. Palvimo
The Nuclear Receptor Interaction Domain of GRIP1 Is Modulated by Covalent Attachment of SUMO-1
J. Biol. Chem., August 9, 2002; 277(33): 30283 - 30288.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
C. Lethimonier, G. Flouriot, O. Kah, and B. Ducouret
The Glucocorticoid Receptor Represses the Positive Autoregulation of the Trout Estrogen Receptor Gene by Preventing the Enhancer Effect of a C/EBP{beta}-Like Protein
Endocrinology, August 1, 2002; 143(8): 2961 - 2974.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
S. S. Koh, H. Li, Y.-H. Lee, R. B. Widelitz, C.-M. Chuong, and M. R. Stallcup
Synergistic Coactivator Function by Coactivator-associated Arginine Methyltransferase (CARM) 1 and beta -Catenin with Two Different Classes of DNA-binding Transcriptional Activators
J. Biol. Chem., July 12, 2002; 277(29): 26031 - 26035.
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J. Biol. Chem.Home page
T. Kucera, M. Waltner-Law, D. K. Scott, R. Prasad, and D. K. Granner
A Point Mutation of the AF2 Transactivation Domain of the Glucocorticoid Receptor Disrupts Its Interaction with Steroid Receptor Coactivator 1
J. Biol. Chem., July 12, 2002; 277(29): 26098 - 26102.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
S. Cheng, S. Brzostek, S. R. Lee, A. N. Hollenberg, and S. P. Balk
Inhibition of the Dihydrotestosterone-Activated Androgen Receptor by Nuclear Receptor Corepressor
Mol. Endocrinol., July 1, 2002; 16(7): 1492 - 1501.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
Y. Maeda, C. Rachez, L. Hawel III, C. V. Byus, L. P. Freedman, and F. M. Sladek
Polyamines Modulate the Interaction between Nuclear Receptors and Vitamin D Receptor-Interacting Protein 205
Mol. Endocrinol., July 1, 2002; 16(7): 1502 - 1510.
[Abstract] [Full Text] [PDF]


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ScienceHome page
B. C. Freeman and K. R. Yamamoto
Disassembly of Transcriptional Regulatory Complexes by Molecular Chaperones
Science, June 21, 2002; 296(5576): 2232 - 2235.
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J. Clin. Endocrinol. Metab.Home page
A. Vottero, T. Kino, H. Combe, P. Lecomte, and G. P. Chrousos
A Novel, C-Terminal Dominant Negative Mutation of the GR Causes Familial Glucocorticoid Resistance through Abnormal Interactions with p160 Steroid Receptor Coactivators
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2658 - 2667.
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Mol. Cell. Biol.Home page
W. Shao, S. Halachmi, and M. Brown
ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator
Mol. Cell. Biol., May 15, 2002; 22(10): 3358 - 3372.
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J. Biol. Chem.Home page
N. Kotaja, M. Vihinen, J. J. Palvimo, and O. A. Janne
Androgen Receptor-interacting Protein 3 and Other PIAS Proteins Cooperate with Glucocorticoid Receptor-interacting Protein 1 in Steroid Receptor-dependent Signaling
J. Biol. Chem., May 10, 2002; 277(20): 17781 - 17788.
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Mol. Cell. Biol.Home page
M. D. Ruse Jr., M. L. Privalsky, and F. M. Sladek
Competitive Cofactor Recruitment by Orphan Receptor Hepatocyte Nuclear Factor 4{alpha}1: Modulation by the F Domain
Mol. Cell. Biol., March 15, 2002; 22(6): 1626 - 1638.
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J. Biol. Chem.Home page
B. He, J. T. Minges, L. W. Lee, and E. M. Wilson
The FXXLF Motif Mediates Androgen Receptor-specific Interactions with Coregulators
J. Biol. Chem., March 15, 2002; 277(12): 10226 - 10235.
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J. Biol. Chem.Home page
H. Liu, W.-C. Park, D. J. Bentrem, K. P. McKian, A. D. L. Reyes, J. A. Loweth, J. M. Schafer, J. W. Zapf, and V. C. Jordan
Structure-Function Relationships of the Raloxifene-Estrogen Receptor-alpha Complex for Regulating Transforming Growth Factor-alpha Expression in Breast Cancer Cells
J. Biol. Chem., March 8, 2002; 277(11): 9189 - 9198.
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Mol. Endocrinol.Home page
J. M. Hall, D. P. McDonnell, and K. S. Korach
Allosteric Regulation of Estrogen Receptor Structure, Function, and Coactivator Recruitment by Different Estrogen Response Elements
Mol. Endocrinol., March 1, 2002; 16(3): 469 - 486.
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Mol. Endocrinol.Home page
R. V. Weatherman, C.-Y. Chang, N. J. Clegg, D. C. Carroll, R. N. Day, J. D. Baxter, D. P. McDonnell, T. S. Scanlan, and F. Schaufele
Ligand-Selective Interactions of ER Detected in Living Cells by Fluorescence Resonance Energy Transfer
Mol. Endocrinol., March 1, 2002; 16(3): 487 - 496.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
S. Fan, Y. X. Ma, C. Wang, R.-Q. Yuan, Q. Meng, J.-A. Wang, M. Erdos, I. D. Goldberg, P. Webb, P. J. Kushner, et al.
p300 Modulates the BRCA1 Inhibition of Estrogen Receptor Activity
Cancer Res., January 1, 2002; 62(1): 141 - 151.
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