The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation.
The polyomavirus middle T antigen (PyMT) oncogene activates the cellular nonreceptor tyrosine kinase c-Src and recruits the Hippo pathway effectors, Yap (yes-associated protein) and Taz (transcriptional coactivator with PDZ-binding motif), as key steps in oncogenesis. Yap and Taz are transcription coactivators shuttling from the cytoplasm to the nucleus. The Hippo pathway kinase Lats1/2 (large tumor suppressor homolog) reduces Yap/Taz nuclear localization and minimizes their cytoplasmic levels by facilitating their ubiquitination by the E3 ligase SCF(β-TrCP). In contrast, PyMT increases the cytoplasmic Taz level. Here we show that this unique PyMT behavior is mediated by Src. We demonstrate that PyMT-induced Src activation inhibits degradation of both wild-type and tyrosine-less Taz, ruling out Taz modification as a mechanism of escaping degradation. Instead, we found that Src attenuates the SCF(β-TrCP) E3-ligase activity in blunting Taz proteasomal degradation. The role of Src in rescuing Taz from TrCP-mediated degradation gives rise to higher cell proliferation under dense cell culture. Finally, IkB (NF-kappa-B inhibitor), a known substrate of β-TrCP, was rescued by Src, suggesting a wider effect of Src on β-TrCP substrates. These findings introduce the Src tyrosine kinase as a regulator of SCF(β-TrCP).
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100.
Matan
M
Shanzer
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100.
Julia
J
Adler
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100.
Inna
I
Ricardo-Lax
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100.
Nina
N
Reuven
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100 yosef.shaul@weizmann.ac.il.
Yosef
Y
Shaul
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D025521:Tumor Suppressor Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
Hippo pathway; SCF(β-TrCP); middle T antigen; viral oncogene; virus host interaction