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

PloS One
Lan Ho WeiNatalia A Riobo-Del Galdo

Abstract

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 ...Continue Reading

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Citations

Feb 23, 2019·Journal of Developmental Biology·Yuan WangAimin Liu
Feb 9, 2019·Nature Reviews. Nephrology·Zeinab AnvarianSøren Tvorup Christensen
May 21, 2019·Frontiers in Aging Neuroscience·Patrícia G de OliveiraSandra I Vieira
Sep 23, 2020·Cells·Daniel DohenyHui-Wen Lo
Apr 6, 2021·World Journal of Hepatology·Yana V KiselevaYuri O Zharikov

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Methods Mentioned

BETA
GTPases
GTPase
pulldown
scraping
pull-down
pulldowns

Software Mentioned

ImageJ

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