TY - JOUR T1 - Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple JF - bioRxiv DO - 10.1101/137125 SP - 137125 AU - Nicolas Aznar AU - Ying Dunkel AU - Nina Sun AU - Kendall Satterfield AU - Fang He AU - Inmaculada Lopez-Sanchez AU - Majid Ghassemian AU - Debashis Sahoo AU - Irina Kufareva AU - Pradipta Ghosh Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/12/137125.abstract N2 - 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 Gαi 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 Gαi 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↔G-protein↔Wnt crosstalk paradigm in cancer biology. ER -