Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia

Lan Ho Wei, Mohammad Arastoo, Ioanna Georgiou, David R. Manning, Natalia Riobo-Del Galdo* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
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Primary cilia are solitary organelles that emanate from the plasma membrane during growth arrest in almost all mammalian cells. The canonical Hedgehog (HH) pathway requires trafficking of the G protein-coupled receptor SMOOTHENED (SMO) and the GLI transcription factors to the primary cilium upon binding of a HH ligand to PATCHED1. However, it is unknown if activation of the small GTPase RHOA by SMO coupling to heterotrimeric Gi proteins, a form of non-canonical HH signaling, requires localization of SMO in the primary cilium. In this study, we compared RHOA and Gi protein stimulation by activation of SMO or sphingosine 1-phosphate receptor (S1P) receptors in WT and KIF3A-deficient mouse embryonic fibroblasts that lack primary cilia. We found that activation of SMO in response to Sonic HH (SHH) or purmorphamine (PUR), a small molecule agonist of SMO, stimulates Gi proteins and RHOA independently of the presence of primary cilia, similar to the effects of S1P. However, while S1P induced a fast activation of AKT that is sensitive to the Gi inhibitor pertussis toxin, HH pathway activators did not significantly activate AKT, suggesting that RHOA activation is not downstream of AKT. Our findings demonstrate that early events in some forms of non-canonical HH signaling occur in extraciliary membranes, which might be particularly relevant for actively-cycling cells, for some cancers characterized by loss of primary cilia, and in ciliopathies.
Original languageEnglish
Article numbere0203170
Number of pages11
JournalPloS ONE
Issue number8
Early online date27 Aug 2018
Publication statusPublished - 27 Aug 2018

Bibliographical note

Funding: The study was funded by the National Institute of General Medical Sciences (2 RO1 GM080396-05A1 to DRM and NARDG; The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.


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