The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling.
Sonic hedgehog (Shh) is a secreted morphogen crucial for cell fate decision, cellular proliferation, and patterning during vertebrate development. The intracellular Shh signalling is transduced by Smoothened (Smo), a seven-transmembrane spanning protein that belongs to the G-protein coupled receptor family. Among four families of Galpha subunits, Galphai has been thought to be responsible for transducing Shh signalling, while several lines of evidence indicated that other signalling pathways may be involved. We found that the G12 family of heterotrimeric G proteins and the small GTPase RhoA are involved in Shh/Smo-mediated cellular responses, including stimulation of target gene promoter and inhibition of neurite outgrowth of neuroblastoma cells. We also found that the G12/RhoA pathway is responsible for Smo-induced nuclear import of GLI3 which is thought to transduce Shh signals to nucleus. Furthermore, misexpression of a G12-specific GTPase-activating protein in rat neural tubes leads to pertubation of motor neurone and interneurone development, mimicking the effects of decreased Shh signalling. These results show that Shh signalling is mediated in part by activating G12 family coupled signalling pathways. The participation of RhoA, a pivotal molecular switch in many signal transduction pathways, may help explain how Shh can trigger a variety of cellular responses.
Kasai
Kenji
K
Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan. kkasai@amugw.aichi-med-u.ac.jp
Takahashi
Masanori
M
Osumi
Noriko
N
Sinnarajah
Srikumar
S
Takeo
Tomohiro
T
Ikeda
Hiroshi
H
Kehrl
John H
JH
Itoh
Gen
G
Arnheiter
Heinz
H
D000818:Animals; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D017930:Genes, Reporter; D053823:Hedgehog Proteins; D006801:Humans; D016501:Neurites / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020741:rho GTP-Binding Proteins