Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats.
We have identified the transforming acidic coiled-coil protein-3 (Tacc3) as a binding partner for Notch4/Int3 and were able to show that it binds to the intracellular domain (ICD) of all members of the Notch receptor family. Members of the Tacc family reside at the centrosomes and associates with microtubules. Recent studies suggest that Tacc3 also contributes to the regulation of gene transcription. Tacc3 specifically interacts with the Notch4/Int3 CDC10/Ankyrin repeats and to a lesser extent, with residues C-terminal to these repeats in the ICD. Dual label immunofluorescence of mouse mammary tissue shows Tacc3 co-localizes with the Notch3 ICD. Co-immunoprecipitation of endogenous Notch and Tacc3 proteins from NIH3T3 cell extracts, lung and mammary gland confirms that these two proteins interact under physiological conditions. In addition, knock down of Tacc3 in NIH3T3 cells leads to the up-regulation of Hey2, a target gene for Notch signaling. The affinity of Tacc3 binding to Notch4/Int3 ICD is similar to that between Rbpj and Notch4/Int3 ICD. Notch4/Int3 ICD-Tacc3 interaction results in the inhibition of transcription from a Hes1-Luciferase reporter vector in COS-1 cells. The inhibition was reversed in these cells by increasing the levels of Rbpj. Taken together, these results suggest that Tacc3 is a negative regulator of the Notch signaling pathway.
Bargo
Sharon
S
Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, MD 20892, USA.
Raafat
Ahmed
A
McCurdy
David
D
Amirjazil
Idean
I
Shu
Youmin
Y
Traicoff
June
J
Plant
Joshua
J
Vonderhaar
Barbara K
BK
Callahan
Robert
R
D000818:Animals; D017089:Ankyrin Repeat; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics; D008156:Luciferases; D051379:Mice; D008869:Microtubule-Associated Proteins; D041681:NIH 3T3 Cells; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000378:metabolism*; D058112:Septins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D020798:Two-Hybrid System Techniques
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D005326:Fetal Proteins; D018398:Homeodomain Proteins; D008156:Luciferases; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D058112:Septins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C418485:TACC3 protein, mouse; C073572:Notch4 protein, mouse; C512895:Sept7 protein, mouse
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