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Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1678-1683. doi: 10.1073/pnas.1610223114. Epub 2017 Feb 1.

The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation.

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100.
2
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel, 76100 yosef.shaul@weizmann.ac.il.

Abstract

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).

KEYWORDS:

Hippo pathway; SCF(β-TrCP); middle T antigen; viral oncogene; virus host interaction

PMID:
28154141
PMCID:
PMC5320963
DOI:
10.1073/pnas.1610223114
[Indexed for MEDLINE]
Free PMC Article

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