Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade.
Numerous studies have demonstrated that estrogens induce rapid and transient activation of the Src/Erk phosphorylation cascade. Activation of this cascade triggers vital cellular functions including cell proliferation and differentiation. However, the details of the molecular mechanism of this process remain to be elucidated. We have identified a previously uncharacterized nuclear receptor-interacting protein designated as modulator of nongenomic activity of estrogen receptor (MNAR). Here we show that MNAR modulates estrogen-receptor (ER) interaction with members of the Src family of tyrosine kinases, which leads to a stimulation of Src enzymatic activity and activation of Erk1 and Erk2 kinases. We also show that MNAR, through activation of the Src/Erk phosphorylation cascade, affects ER transcriptional activity and ultimately ER-mediated gene expression. These data reveal that MNAR mediates the crosstalk between two important classes of signal transducing molecules and suggest that ER "genomic" and "nongenomic" activities are interrelated.
Wong
Chi-Wai
CW
Department of Cell Biology, Women's Health Research Institute, Wyeth Pharmaceuticals, 500 Arcolla Road, Collegeville, PA 19426, USA.
McNally
Christopher
C
Nickbarg
Elliot
E
Komm
Barry S
BS
Cheskis
Boris J
BJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms; D003001:Cloning, Molecular; D017931:DNA Primers; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D020239:Receptor Cross-Talk / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism*
D017931:DNA Primers; D047628:Estrogen Receptor alpha; D015345:Oligonucleotide Probes; D010446:Peptide Fragments; D011960:Receptors, Estrogen; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases