TMF/ARA160 is a BC-box-containing protein that mediates the degradation of Stat3.
TMF/ARA160 is a Golgi resident protein whose cellular functions have not been conclusively revealed. Herein we show that TMF/ARA160 can direct the proteasomal degradation of the key cell growth regulator - Stat3. TMF/ARA160 was dispersed in the cytoplasm of myogenic C2C12 cells that were grown under low-serum conditions. The cytoplasmic distribution of TMF/ARA160 was accompanied by its transient association with the tyrosine kinase Fer and with Stat3, which underwent proteasomal degradation under those conditions. Moreover, serum deprivation induced the association of ubiquitinated proteins, with the TMF/ARA160 complex. However, TMF/ARA160 did not bind Stat1, whose cellular levels were increased in serum-starved C2C12 cells. Amino-acid sequence analysis identified a BC-box element in TMF/ARA160 that mediated the binding of this protein to elongin C. Ectopic expression of TMF/ARA160 in serum-starved C2C12 cells drove the ubiquitination and proteasomal degradation of Stat3, an effect that was not caused by TMF/ARA160 devoid of the BC-box motif. Thus, the Golgi apparatus harbors a novel BC-box-containing protein that can direct Stat3 to proteasomal degradation. Interestingly, the level of TMF/ARA160 was significantly decreased in malignant brain tumors, implying a suppressive role of that protein in tumor progression.
Perry
Erez
E
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Tsruya
Rachel
R
Levitsky
Pavel
P
Pomp
Oz
O
Taller
Michal
M
Weisberg
Shira
S
Parris
Wendy
W
Kulkarni
Sarang
S
Malovani
Hana
H
Pawson
Tony
T
Shpungin
Sally
S
Nir
Uri
U
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism; D002460:Cell Line; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D015536:Down-Regulation; D000075065:Elongin; D006056:Golgi Apparatus / Q000378:metabolism; D000077614:Golgi Matrix Proteins; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D019000:Phosphotyrosine / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D015534:Trans-Activators; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; C000616395:ELOC protein, human; C000616411:Eloc protein, mouse; D000075065:Elongin; D000077614:Golgi Matrix Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C554202:Tmf1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025801:Ubiquitin; D033921:Vesicular Transport Proteins; C052602:proto-oncogene protein c-fes-fps; C077335:TMF1 protein, human; D019000:Phosphotyrosine; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex