title: The PI3K/Akt signal hyperactivates Eya1 via the SUMOylation pathway.
abstract: Eyes absent 1 (Eya1) is a conserved critical regulator of organ-specific stem cells. Ectopic Eya1 activities, however, promote transformation of mammary epithelial cells. Signals that instigate Eya1 oncogenic activities remain to be determined. Here, we show that Akt1 kinase physically interacts with Eya1 and phosphorylates a conserved consensus site of the Akt kinase. PI3K/Akt signaling enhances Eya1 transcription activity, which largely attributes to the phosphorylation-induced reduction of Eya1 SUMOylation. Indeed, SUMOylation inhibits Eya1 transcription activity; and pharmacologic and genetic activation of PI3K/Akt robustly reduces Eya1 SUMOylation. Wild-type but not Akt phosphorylation site mutant Eya1 variant rescues the cell migratory phenotype of EYA1-silenced breast cancer cells, highlighting the importance of Eya1 phosphorylation. Furthermore, knockdown EYA1 sensitizes breast cancer cells to the PI3K/Akt1 inhibitor and irradiation treatments. Thus, the PI3K/Akt signal pathway activates Eya1. These findings further suggest that regulation of SUMOylation by PI3K/Akt signaling is likely an important aspect of tumorigenesis.
authors: 1] Urological Diseases Research Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, USA [2] Departments of Surgery and Pathology, Harvard Medical School, Boston, MA, USA.
authors: Y
authors: Y
authors: Sun
authors: 1] Urological Diseases Research Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, USA [2] Departments of Surgery and Pathology, Harvard Medical School, Boston, MA, USA.
authors: S
authors: S
authors: Kaneko
authors: School of Pharmaceutical Science, Wenzhou Medical College, Wenzhou, China.
authors: X K
authors: XK
authors: Li
authors: 1] Urological Diseases Research Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, USA [2] Departments of Surgery and Pathology, Harvard Medical School, Boston, MA, USA.
authors: X
authors: X
authors: Li
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D058207:Sumoylation; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases