title: Metastatic tumor antigen 1 short form (MTA1s) associates with casein kinase I-gamma2, an estrogen-responsive kinase.
abstract: Recent studies have shown that metastasis-associated protein-1 short form (MTA1s) - metastatic tumor antigen 1 short form sequesters estrogen receptor-alpha (ER-alpha) in the cytoplasm of breast cancer cells. Using a yeast two-hybrid screening to clone MTA1s-interacting proteins, we identified casein kinase I-gamma 2 (CKI-gamma2, a ubiquitously expressed cytoplasmic kinase) as an MTA1s-binding protein. We show that MTA1s interacts with CKI-gamma2 both in vitro and in vivo and colocalizes in the cytoplasm. In addition, we found that CKI-gamma2 can phosphorylate MTA1s, but not ER, in an antiestrogen-dependent manner and that estrogen stimulates CKI-gamma2 activity that could be effectively blocked by a specific inhibitor of CKI. CKI-gamma2 could further potentiate the ER corepressive function of MTA1s. Kinase dead CK1-gamma2 could not repress estrogen-induced ER transactivation functions. Results from mutagenesis studies suggest that substitution of the serine residue at 321 to alanine, which is a possible CKI-gamma2 phopshorylation site in MTA1s, results in a significant reduction in the ability of MTA1s to repress ER transactivation. These findings identified MTA1s as a target of CKI-gamma2, and provided new evidence to suggest that CKI-gamma2 phosphorylates and modulates the functions of MTA1s, and that these extranuclear effects of estrogen might have important implications in regulating the functions of MTA1s in human mammary epithelial and cancer cells.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Mishra
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yang
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mazumdar
authors.forename: Amjad H
authors.initials: AH
authors.lastname: Talukder
authors.forename: Louise
authors.initials: L
authors.lastname: Larose
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology; D047388:Casein Kinases; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015534:Trans-Activators; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; C089320:MTA1 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D004958:Estradiol; D005982:Glutathione Transferase; D011494:Protein Kinases; D047388:Casein Kinases; D006655:Histone Deacetylases