ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression.
ErbB-4 is cleaved by alpha- and gamma-secretases to release a soluble 80-kDa intracellular domain, termed s80, which translocates to the nucleus. s80 is present in the nucleus of normal and cancerous mammary cells and is predicted to have a role in cell differentiation. To further investigate the mechanism by which s80 may mediate differentiation, we tested whether s80 regulates Eto2, a transcriptional corepressor that is involved in erythrocyte differentiation and is also implicated in human breast cancer. Here we show that ligand binding to ErbB-4 causes s80 translocation to the nucleus, where it colocalizes and interacts with Eto2. Expression of s80 blocks Eto2-mediated transcriptional repression of a heterologous promoter. This effect on Eto2 does not require s80 kinase activity and is mediated by the carboxyl-terminal region of s80. Although other cell surface receptors regulate transcription by activating signal transduction cascades, these data present a novel mechanism of corepressor regulation and suggest a role for Eto2 in ErbB-4-dependent differentiation.
Linggi
Bryan
B
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Carpenter
Graham
G
D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000737:chemistry / Q000502:physiology*; D004912:Erythrocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C115744:CBFA2T3 protein, human; D010750:Phosphoproteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4