Signaling Within a Coactivator Complex: Methylation of SRC-3/AIB1 is a Molecular Switch for Complex Disassembly

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2006 Aug 23

PMID 16923966

Citations 94

Authors

Qin Feng

Ping Yi

Jiemin Wong

Bert W OMalley

Affiliations

Soon will be listed here.

Abstract

Recent studies indicate that steroid receptor-mediated transcriptional initiation is a cyclical process involving multiple rounds of coactivator assembly and disassembly. Steroid receptor coactivator 3 (SRC-3) coactivator phosphorylation has been shown to regulate coactivator complex assembly, but the mechanisms by which coactivator disassembly is triggered are not well understood. In this study, we provide in vitro and in vivo evidence that members of the SRC coactivator family serve as substrates for the enzymatic coactivator coactivator-associated arginine methyltransferase 1 (CARM1). Methylation of SRC-3 was localized to an arginine in its CARM1 binding region and correlated with decreased estrogen receptor alpha-mediated transcription, as seen with both cell-based and in vitro transcription assays. Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex. Methylation of SRC-3 is regulated by estrogen signaling in MCF7 cells and serves as a molecular switch for disassembly of the SRC-3 transcriptional coactivator complex. We propose that CARM1 is a dual-function coactivator, as it not only activates transcription by modifying core histone tails but also terminates hormone signaling by disassembly of the coactivator complex.

Citing Articles

Design, synthesis and evaluation of pyrimidinobenzylamide and pyrimidinothiophenamide derivatives as inhibitors of DOT1L and related epigenetic targets DNMT3a, PRMT4 and other HMTs.

Castillo-Aguilera O, Depreux P, Halby L, Bailly C, Dominguez-Ramirez L, Gul S RSC Med Chem. 2025; .

PMID: 40061000 PMC: 11886420. DOI: 10.1039/d4md00899e.

PRMT3 and CARM1: Emerging Epigenetic Targets in Cancer.

Huang J, Qiao B, Yuan Y, Xie Y, Xia X, Li F J Cell Mol Med. 2025; 29(4):e70386.

PMID: 39964832 PMC: 11834966. DOI: 10.1111/jcmm.70386.

Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity.

Itonaga H, Mookhtiar A, Greenblatt S, Liu F, Martinez C, Bilbao D Nat Commun. 2024; 15(1):3415.

PMID: 38649367 PMC: 11035800. DOI: 10.1038/s41467-024-47689-4.

The emerging role of CARM1 in cancer.

Xie Z, Tian Y, Guo X, Xie N Cell Oncol (Dordr). 2024; 47(5):1503-1522.

PMID: 38619752 PMC: 11466993. DOI: 10.1007/s13402-024-00943-9.

Control of protein stability by post-translational modifications.

Lee J, Hammaren H, Savitski M, Baek S Nat Commun. 2023; 14(1):201.

PMID: 36639369 PMC: 9839724. DOI: 10.1038/s41467-023-35795-8.

References

Yi P, Wu R, Sandquist J, Wong J, Tsai S, Tsai M . Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1). Mol Cell Biol. 2005; 25(21):9687-99. PMC: 1265806. DOI: 10.1128/MCB.25.21.9687-9699.2005. View

Kuang S, Liao L, Zhang H, Lee A, OMalley B, Xu J . AIB1/SRC-3 deficiency affects insulin-like growth factor I signaling pathway and suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Cancer Res. 2004; 64(5):1875-85. DOI: 10.1158/0008-5472.can-03-3745. View

Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung Y . Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol Cell Biol. 2002; 22(10):3373-88. PMC: 133781. DOI: 10.1128/MCB.22.10.3373-3388.2002. View

McKenna N, OMalley B . Combinatorial control of gene expression by nuclear receptors and coregulators. Cell. 2002; 108(4):465-74. DOI: 10.1016/s0092-8674(02)00641-4. View

Dickson R, Stancel G . Estrogen receptor-mediated processes in normal and cancer cells. J Natl Cancer Inst Monogr. 2000; (27):135-45. DOI: 10.1093/oxfordjournals.jncimonographs.a024237. View

Lee D, Teyssier C, Strahl B, Stallcup M . Role of protein methylation in regulation of transcription. Endocr Rev. 2004; 26(2):147-70. DOI: 10.1210/er.2004-0008. View

Katzenellenbogen B, Katzenellenbogen J . Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res. 2001; 2(5):335-44. PMC: 138655. DOI: 10.1186/bcr78. View

Lee Y, Koh S, Zhang X, Cheng X, Stallcup M . Synergy among nuclear receptor coactivators: selective requirement for protein methyltransferase and acetyltransferase activities. Mol Cell Biol. 2002; 22(11):3621-32. PMC: 133819. DOI: 10.1128/MCB.22.11.3621-3632.2002. View

Gu W, Roeder R . Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell. 1997; 90(4):595-606. DOI: 10.1016/s0092-8674(00)80521-8. View

10.

Anzick S, Kononen J, Walker R, Azorsa D, TANNER M, Guan X . AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science. 1997; 277(5328):965-8. DOI: 10.1126/science.277.5328.965. View

11.

Zheng F, Wu R, Smith C, OMalley B . Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor. Mol Cell Biol. 2005; 25(18):8273-84. PMC: 1234335. DOI: 10.1128/MCB.25.18.8273-8284.2005. View

12.

Shang Y, Hu X, DiRenzo J, Lazar M, Brown M . Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell. 2001; 103(6):843-52. DOI: 10.1016/s0092-8674(00)00188-4. View

13.

Wang C, Fu M, Angeletti R, Reutens A, Albanese C, Lisanti M . Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 2001; 276(21):18375-83. DOI: 10.1074/jbc.M100800200. View

14.

Li H, Gomes P, Chen J . RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A. 1997; 94(16):8479-84. PMC: 22964. DOI: 10.1073/pnas.94.16.8479. View

15.

Spencer T, Jenster G, Burcin M, Allis C, Zhou J, Mizzen C . Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997; 389(6647):194-8. DOI: 10.1038/38304. View

16.

Freeman B, Yamamoto K . Disassembly of transcriptional regulatory complexes by molecular chaperones. Science. 2002; 296(5576):2232-5. DOI: 10.1126/science.1073051. View

17.

Wu R, Qin J, Yi P, Wong J, Tsai S, Tsai M . Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways. Mol Cell. 2004; 15(6):937-49. DOI: 10.1016/j.molcel.2004.08.019. View

18.

Voegel J, Heine M, Zechel C, Chambon P, Gronemeyer H . TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996; 15(14):3667-75. PMC: 452006. View

19.

Barlev N, Liu L, Chehab N, Mansfield K, Harris K, Halazonetis T . Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol Cell. 2002; 8(6):1243-54. DOI: 10.1016/s1097-2765(01)00414-2. View

20.

Chen H, Lin R, Schiltz R, Chakravarti D, Nash A, Nagy L . Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997; 90(3):569-80. DOI: 10.1016/s0092-8674(00)80516-4. View