Sonic Hedgehog Signaling

Sonic hedgehog homolog (SHH) is one of three proteins the mammalian hedgehog family that patterns and specifies cell fate in several different tissues. SHH is a secreted protein that triggers a cascade of events in target cells leading to the regulation of transcription by the GLI family of trans factors. This results in the expression or repression of several genes that are crucial in the normal development of an embryo.In the absence of its ligand SHH, the 12 span transmembrane protein PATCHED (PTCH) inhibits a 7 span transmembrane protein SMOOTHENED (SMO). The inhibition of SMO is relieved in the presence of SHH. Activated SMO then inhibits the suppressor of fused protein (SuFu) which results in the transcriptional response to SHH mediated by the GLI family of trans factors. The transcriptional activity of GLI is modulated by several factors like protein kinase A (PKA) and glycogen synthase kinase beta (GSKβ). Other proteins like G protein-coupled receptor kinase 2 (GRK2) and beta-Arrestin 2 (ARRB2) activate GLI mediated transcriptional activity by phosphorylating and binding to SMO respectively. In addition to relieving the inhibition of GLI mediated transcriptional activity, SHH also relieves PTCH mediated inhibition of cell cycle kinase CDC2/cyclinB1, thus allowing cell cycle progression.Patched and Smoothened may shuttle oppositely between the plasma membrane and endosomes in response to SHH.This pathway highlights some important molecular events in Sonic Hedgehog protein signaling.