PMID- 21695114
OWN - NLM
STAT- MEDLINE
DCOM- 20111027
LR  - 20240410
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 9
IP  - 6
DP  - 2011 Jun
TI  - Sonic Hedgehog dependent phosphorylation by CK1alpha and GRK2 is required for ciliary 
      accumulation and activation of smoothened.
PG  - e1001083
LID - 10.1371/journal.pbio.1001083 [doi]
LID - e1001083
AB  - Hedgehog (Hh) signaling regulates embryonic development and adult tissue 
      homeostasis through the GPCR-like protein Smoothened (Smo), but how vertebrate 
      Smo is activated remains poorly understood. In Drosophila, Hh dependent 
      phosphorylation activates Smo. Whether this is also the case in vertebrates is 
      unclear, owing to the marked sequence divergence between vertebrate and 
      Drosophila Smo (dSmo) and the involvement of primary cilia in vertebrate Hh 
      signaling. Here we demonstrate that mammalian Smo (mSmo) is activated through 
      multi-site phosphorylation of its carboxyl-terminal tail by CK1alpha and GRK2. 
      Phosphorylation of mSmo induces its active conformation and simultaneously 
      promotes its ciliary accumulation. We demonstrate that graded Hh signals induce 
      increasing levels of mSmo phosphorylation that fine-tune its ciliary 
      localization, conformation, and activity. We show that mSmo phosphorylation is 
      induced by its agonists and oncogenic mutations but is blocked by its antagonist 
      cyclopamine, and efficient mSmo phosphorylation depends on the kinesin-II ciliary 
      motor. Furthermore, we provide evidence that Hh signaling recruits CK1alpha to 
      initiate mSmo phosphorylation, and phosphorylation further increases the binding 
      of CK1alpha and GRK2 to mSmo, forming a positive feedback loop that amplifies and/or 
      sustains mSmo phosphorylation. Hence, despite divergence in their primary 
      sequences and their subcellular trafficking, mSmo and dSmo employ analogous 
      mechanisms for their activation.
FAU - Chen, Yongbin
AU  - Chen Y
AD  - Department of Developmental Biology, University of Texas Southwestern Medical 
      Center at Dallas, United States of America.
FAU - Sasai, Noriaki
AU  - Sasai N
FAU - Ma, Guoqiang
AU  - Ma G
FAU - Yue, Tao
AU  - Yue T
FAU - Jia, Jianhang
AU  - Jia J
FAU - Briscoe, James
AU  - Briscoe J
FAU - Jiang, Jin
AU  - Jiang J
LA  - eng
GR  - R01 GM067045/GM/NIGMS NIH HHS/United States
GR  - R01 GM079684/GM/NIGMS NIH HHS/United States
GR  - GM079684/GM/NIGMS NIH HHS/United States
GR  - GM61269/GM/NIGMS NIH HHS/United States
GR  - R01 GM061269/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110614
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Smo protein, mouse)
RN  - 0 (Smoothened Receptor)
RN  - EC 2.7.11.1 (Casein Kinase Ialpha)
RN  - EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
SB  - IM
EIN - EMBO Rep. 2021 May 5;22(5):e52895. PMID: 33949092
MH  - Animals
MH  - Casein Kinase Ialpha/*metabolism
MH  - Cell Membrane/metabolism
MH  - Cells, Cultured
MH  - Cilia/metabolism
MH  - Drosophila/genetics/metabolism
MH  - G-Protein-Coupled Receptor Kinase 2/*metabolism
MH  - Hedgehog Proteins/*metabolism
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Phosphorylation
MH  - Receptors, G-Protein-Coupled/*metabolism
MH  - Signal Transduction
MH  - Smoothened Receptor
MH  - Transfection
PMC - PMC3114773
COIS- The authors have declared that no competing interests exist.
EDAT- 2011/06/23 06:00
MHDA- 2011/10/28 06:00
PMCR- 2011/06/14
CRDT- 2011/06/23 06:00
PHST- 2011/01/11 00:00 [received]
PHST- 2011/05/05 00:00 [accepted]
PHST- 2011/06/23 06:00 [entrez]
PHST- 2011/06/23 06:00 [pubmed]
PHST- 2011/10/28 06:00 [medline]
PHST- 2011/06/14 00:00 [pmc-release]
AID - PBIOLOGY-D-11-00125 [pii]
AID - 10.1371/journal.pbio.1001083 [doi]
PST - ppublish
SO  - PLoS Biol. 2011 Jun;9(6):e1001083. doi: 10.1371/journal.pbio.1001083. Epub 2011 
      Jun 14.