Gli Protein Activity Is Controlled by Multisite Phosphorylation in Vertebrate Hedgehog Signaling
Open accessAbstract
Gli proteins are transcriptional effectors of the Hedgehog (Hh) pathway in both normal development and cancer. We describe a program of multisite phosphorylation that regulates the conversion of Gli proteins into transcriptional activators. In the absence of Hh ligands, Gli activity is restrained by the direct phosphorylation of six conserved serine residues by protein kinase A (PKA), a master negative regulator of the Hh pathway. Activation of signaling leads to a global remodeling of the Gli phosphorylation landscape: the PKA target sites become dephosphorylated, while a second cluster of sites undergoes phosphorylation. The pattern of Gli phosphorylation can regulate Gli transcriptional activity in a graded fashion, suggesting a phosphorylation-based mechanism for how a gradient of Hh signaling in a morphogenetic field can be converted into a gradient of transcriptional activity.
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Downstream factors that mediate SMO-dependent activation of GLI2 are varied and include G proteins and other proteins such as the EVC2 complex.
“Downstream factors that mediate SMO-dependent activation of GLI2 are varied, and include G proteins and other proteins such as the EVC2 complex 104, 115.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [104]
The Introduction (page unavailable) describes Smoothened as controlling Gli activator production, and the Results section on Gli2 transcriptional activity shows that Smoothened signaling regulates Gli2. But the paper does not identify G proteins or the EVC2 complex as downstream mediators; searches for EVC2 and G proteins found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBasal repression in the absence of SHH involves PKA-mediated phosphorylation predominantly of GLI3 and formation of the truncated N-terminal GLI repressor in a cilia-dependent manner.
“In contrast, basal repression in the absence of SHH involves protein kinase A (PKA)-mediated phosphorylation, predominantly of GLI3, and formation of the truncated N-terminal form of GLI, GLIR, in a cilia-dependent manner 104.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [104]
The Introduction says that when Hedgehog signaling is off, Gli2/3 become truncated repressors; the Results identify Gli3 as the major repressor in most tissues and show PKA-dependent truncation of Gli3 in unstimulated cells. The Introduction discusses ciliary Smoothened inhibiting repressor formation after Hedgehog stimulation, but the passages do not establish that basal repressor formation itself is cilia-dependent. Page numbers are unavailable in our copy. (LLM, conf=0.84)
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- Authors
- Niewiadomski, P., Kong, J. H., Ahrends, R., Ma, Y., Humke, E. W., Khan, S., Teruel, M. N., Novitch, B. G., & Rohatgi, R.
- Affiliations
- University of California, Los Angeles (US)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Stanford Medicine (US)
- Corresponding author
- Rohatgi, Rajat
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 6
- Issue
- 1
- Pages
- 168-181
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3915062
- OpenAlex
- W2066711817
- Cited by
- 239
- References
- 57
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 16 · 2023: 13 · 2022: 18 · 2021: 30 · 2020: 22 · 2019: 25 · 2018: 18 · 2017: 14 · 2016: 16 · 2015: 20 · 2014: 15
- FWCI
- 8.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- RENATE (submittedVersion, cc-by-nc-nd)
- RENATE
- Funders
- National Cancer Institute (R00CA129174)
- National Institute of General Medical Sciences (P50GM107615)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101743)
- National Institute of Neurological Disorders and Stroke (R21NS074091, R01NS053976, R01NS072804)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- Gli proteins, Hedgehog signaling, multisite phosphorylation, protein kinase A, transcriptional activation, morphogen gradients, vertebrate development, cancer
- MeSH terms
- Zinc Finger Protein Gli3, Zinc Finger Protein Gli2, Animals, Chick Embryo, Humans, Nerve Tissue Proteins, Phosphorylation, Protein Binding, Serine, Signal Transduction, Protein Structure, Tertiary, Cyclic AMP-Dependent Protein Kinases, NIH 3T3 Cells, Mice, Kruppel-Like Transcription Factors, Hedgehog Proteins, HEK293 Cells
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