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Convergence of Wnt, Growth Factor and Trimeric G‐protein Signals on the Signaling Scaffold Daple
Author(s) -
Ear Jason,
Aznar Nicolas,
Dunkel Ying,
Sun Nina,
Satterfield Kendall,
He Fang,
LopezSanchez Inmaculada,
Ghassemian Majid,
Sahoo Debashis,
Kufareva Irina,
Ghosh Pradipta
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.533.37
Subject(s) - wnt signaling pathway , frizzled , microbiology and biotechnology , signal transduction , receptor tyrosine kinase , lrp6 , dishevelled , scaffold protein , chemistry , cancer research , guanine nucleotide exchange factor , beta catenin , biology , signal transducing adaptor protein
Aberrant signal transduction is a hallmark of cancer biology. Pathways commonly deregulated include G‐protein signaling, Wnt signaling, and Receptor Tyrosine kinase (RTK) signaling. While typically studied individually, a growing amount of evidence indicate that these pathways are intertwined. Recent studies have demonstrated that Daple ( CCDC88A ) is multimodular domain containing protein that can tether various pathways together, and plays a major role in colorectal cancer (CRCs) progression. Daple is a Dishevelled (Dvl)‐ and Frizzled (FZD) ‐binding protein and a guanine‐nucleotide exchange factor (GEF) for the trimeric G protein, Gαi. Daple enhances β‐catenin‐independent (non‐canonical) Wnt signaling through its ability to activate the pathway downstream of FZD7 upon Wnt5a stimulation. Here we identified that Daple is a substrate of multiple RTKs and non‐RTKs, and hence, can serve as a point of convergence for all three signaling cascades. We show that phosphorylation by both RTKs and non‐RTKs near the atypical PDZ‐binding motif (PBM) on Daple dissociated the Daple:Dvl complexes and augmented the ability of Daple to bind and activate Gαi; which potentiated β‐catenin‐independent Wnt signals and triggered epithelial‐mesenchymal transition (EMT) in a manner similar to that triggered by Wnt5a/FZD7. Although Daple acts as a tumor suppressor in the healthy colon, concurrent upregulation of Daple and the prototype RTK, epidermal growth factor receptor (EGFR), in colorectal tumors from patients was associated with poor prognosis. We conclude that Daple‐dependent activation of Gαi and enhancement of β‐catenin‐independent Wnt signals is not just triggered by Wnt5a/FZD7 to suppress tumorigenesis, but also is hijacked by growth factor‐RTKs to stoke tumor progression. Thus, this work defines a previously unknown crosstalk paradigm amongst growth factor RTKs, trimeric G‐proteins, and Wnt/FZD in cancer biology. Support or Funding Information This work was supported by NIH grants CA100768, CA160911 and DK099226 (to P.G). P.G. was also supported by the American Cancer Society (ACS‐IRG 70‐002) and by the UC San Diego Moores Cancer Center. J.E is supported by an NIH‐institutional training grant (2T32CA067754‐21A1). I.K. was supported by NIH grants GM071872, AI118985, and GM117424. I.L‐S was supported by a fellowship from the American Heart Association (AHA #14POST20050025). F.H was supported by the State Scholarship Fund of China Scholarship Council (No.201208510048) and fund from West China Hospital, Sichuan University, PR China, during her tenure as a visiting professor to UCSD. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .