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PMID:19684112

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Citation

Chen, MH, Wilson, CW, Li, YJ, Law, KK, Lu, CS, Gacayan, R, Zhang, X, Hui, CC and Chuang, PT (2009) Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev. 23:1910-28

Abstract

A central question in Hedgehog (Hh) signaling is how evolutionarily conserved components of the pathway might use the primary cilium in mammals but not fly. We focus on Suppressor of fused (Sufu), a major Hh regulator in mammals, and reveal that Sufu controls protein levels of full-length Gli transcription factors, thus affecting the production of Gli activators and repressors essential for graded Hh responses. Surprisingly, despite ciliary localization of most Hh pathway components, regulation of Gli protein levels by Sufu is cilium-independent. We propose that Sufu-dependent processes in Hh signaling are evolutionarily conserved. Consistent with this, Sufu regulates Gli protein levels by antagonizing the activity of Spop, a conserved Gli-degrading factor. Furthermore, addition of zebrafish or fly Sufu restores Gli protein function in Sufu-deficient mammalian cells. In contrast, fly Smo is unable to translocate to the primary cilium and activate the mammalian Hh pathway. We also uncover a novel positive role of Sufu in regulating Hh signaling, resulting from its control of both Gli activator and repressor function. Taken together, these studies delineate important aspects of cilium-dependent and cilium-independent Hh signal transduction and provide significant mechanistic insight into Hh signaling in diverse species.

Links

PubMed PMC2725943 Online version:10.1101/gad.1794109

Keywords

Animals; Axin Protein; Cell Line, Transformed; Cilia/metabolism; Drosophila; Drosophila Proteins/metabolism; Evolution, Molecular; Hedgehog Proteins/physiology; Humans; Kruppel-Like Transcription Factors/metabolism; Mice; Nerve Tissue Proteins/metabolism; Nuclear Proteins/metabolism; Receptors, Cell Surface/genetics; Receptors, G-Protein-Coupled/deficiency; Receptors, G-Protein-Coupled/metabolism; Repressor Proteins/genetics; Repressor Proteins/metabolism; Signal Transduction; Up-Regulation; Zebrafish; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:KIF3A

acts_upstream_of_or_within

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI1

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI1

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SMO

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q6ZWS8

F

Seeded From UniProt

complete

MOUSE:GLI2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

located_in

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:PTC1

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0060831: smoothened signaling pathway involved in dorsal/ventral neural tube patterning

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857447

P

  • occurs_in:(EMAPA:16530)

Seeded From UniProt

complete

MOUSE:GLI3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q6ZWS8

F

Seeded From UniProt

complete

MOUSE:GLI3

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI3

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI3

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI3

located_in

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SPOP

acts_upstream_of_or_within

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SPOP

located_in

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SPOP

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q0VGT2
PR:Q61602

F

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:0021776: smoothened signaling pathway involved in spinal cord motor neuron cell fate specification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4840420

P

  • occurs_in:(CL:0000100)
  • occurs_in:(EMAPA:16530)

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:0021775: smoothened signaling pathway involved in ventral spinal cord interneuron specification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4840420

P

  • occurs_in:(CL:0000099)
  • occurs_in:(EMAPA:16530)

Seeded From UniProt

complete

MOUSE:SUFU

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SUFU

located_in

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:1901621: negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4840420

P

  • regulates_o_occurs_in:(EMAPA:16530)

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI2

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SMO

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:KIF3A

acts_upstream_of_or_within

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:PTC1

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:PTC1

acts_upstream_of_or_within

GO:0060831: smoothened signaling pathway involved in dorsal/ventral neural tube patterning

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857447

P

occurs_in:(EMAPA:16530)

Seeded From UniProt

complete

MOUSE:GLI3

part_of

GO:0016607: nuclear speck

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI3

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI3

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:1901621: negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4840420

P

regulates_o_occurs_in:(EMAPA:16530)

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:2000059: negative regulation of ubiquitin-dependent protein catabolic process

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1343085

P

Seeded From UniProt

complete

MOUSE:SUFU

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SUFU

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:0021775: smoothened signaling pathway involved in ventral spinal cord interneuron specification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4840420

P

  • occurs_in:(EMAPA:16530)
  • occurs_in:(CL:0000099)

Seeded From UniProt

complete

MOUSE:SUFU

acts_upstream_of_or_within

GO:0021776: smoothened signaling pathway involved in spinal cord motor neuron cell fate specification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4840420

P

  • occurs_in:(EMAPA:16530)
  • occurs_in:(CL:0000100)

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005929: cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)|part_of:(CL:0000057)

Seeded From UniProt

complete

MOUSE:GLI1

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete


See also

References

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