WNT-3A–induced β-catenin signaling does not require signaling through heterotrimeric G proteins

Carl Fredrik Bowin, Asuka Inoue, Gunnar Schulte

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


The network of Wingless/Int-1 (WNT)-induced signaling pathways includes βcatenin–dependent and–independent pathways. β-catenin regulates T cell factor/lymphoid enhancer–binding factor (TCF/LEF)-mediated gene transcription, and in response to WNTs, β-catenin signaling is initiated through engagement of a Frizzled (FZD)/LDL receptor–related protein 5/6 (LRP5/6) receptor complex. FZDs are G protein–coupled receptors, but the question of whether heterotrimeric G proteins are involved in WNT-catenin signaling remains unanswered. Here, we investigate whether acute activation of WNT-catenin signaling by purified WNT-3A requires functional signaling through heterotrimeric G proteins. Using genome editing, we ablated expression of Gs/Golf/Gq/G11/G12/G13/Gz in HEK293 (G7) cells, leaving the expression of pertussis toxin (PTX)-sensitive Gi/o proteins unchanged, to assess whether WNT-3A activates WNT-catenin signaling in WT and G7 cells devoid of functional G protein signaling. We monitored WNT-3A–induced activation by detection of phosphorylation of LDL receptor–related protein 6 (LRP6), electrophoretic mobility shift of the phosphoprotein Dishevelled (DVL), β-catenin stabilization and dephosphorylation, and TCF-dependent transcription. We found that purified, recombinant WNT-3A efficiently induces WNT-catenin signaling in G7 cells in both the absence and presence of Gi/o-blocking PTX. Furthermore, cells completely devoid of G protein expression, so called G-depleted HEK293 cells, maintain responsiveness to WNT-3A with regard to the hallmarks of WNT-catenin signaling. These findings corroborate the concept that heterotrimeric G proteins are not required for this FZD- and DVL-mediated signaling branch. Our observations agree with previous results arguing for FZD conformation–dependent functional selectivity between DVL and heterotrimeric G proteins. In conclusion, WNT-catenin signaling through FZDs does not require the involvement of heterotrimeric G proteins.

Original languageEnglish
Pages (from-to)11677-11684
Number of pages8
JournalJournal of Biological Chemistry
Issue number31
Publication statusPublished - 2019 Aug 2


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