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bioRxiv · 10.1101/137125

Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple

Aznar, N.·Dunkel, Y.·Sun, N.·Satterfield, K.·He, F.·Lopez-Sanchez, I.·Ghassemian, M.·Sahoo, D.·Kufareva, I.·Ghosh, P.
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Abstract

Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades; their concurrent dysregulation plays an integral role in cancer progression and is a common feature of many malignancies. Three such cascades that contribute to the oncogenic potential are the Wnt/Frizzled(FZD), growth factor-receptor tyrosine kinases (RTKs), and G-proteins/GPCRs. Here we identify Daple, a modulator of trimeric G-proteins and a Dishevelled (Dvl)-binding protein as an unexpected point of convergence for all three cascades. Daple-dependent activation of Gi and enhancement of non-canonical Wnt signals is not just triggered by Wnt5a/FZD to suppress tumorigenesis, but also hijacked by growth factor-RTKs to stoke tumor progression. Phosphorylation of Daple by both RTKs and non-RTKs triggers Gi activation and potentiates non-canonical Wnt signals that trigger epithelial-mesenchymal transition. In patients with colorectal cancers, concurrent upregulation of Daple and the prototype RTK, EGFR, carried poor prognosis. Thus, this work defines a novel growth factor{leftrightarrow}G-protein{leftrightarrow}Wnt crosstalk paradigm in cancer biology.

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Aznar, N., Dunkel, Y., Sun, N., Satterfield, K., He, F., Lopez-Sanchez, I., Ghassemian, M., Sahoo, D., Kufareva, I., Ghosh, P.. 2017-06-12. Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple. https://doi.org/10.1101/137125

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