Advertisement
No access
Research Article
Developmental Biology

Hedgehog induces formation of PKA-Smoothened complexes to promote Smoothened phosphorylation and pathway activation

Science Signaling
1 Jul 2014
Vol 7, Issue 332
p. ra62

PKA Switches Partners to Promote Hedgehog Signaling

Hedgehog is a secreted protein that controls developmental patterning and cell fate specification. Hedgehog binds to the transmembrane receptor Patched to relieve inhibition of the seven-transmembrane protein Smoothened (Smo), which in turn activates the transcription factor Ci by inhibiting its phosphorylation by the kinase PKA. Li et al. found that, in fruit flies, activated Smo directly bound to and was phosphorylated by the catalytic subunit of PKA. Phosphorylated Smo recruited more of the catalytic subunit of PKA, which prevented the interaction between PKA and Ci, enabling Ci to activate Hedgehog-regulated genes. Thus, this switching of PKA-substrate interactions controls activation of Hedgehog signaling.

Abstract

Hedgehog (Hh) is a secreted glycoprotein that binds its receptor Patched to activate the G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor–like protein Smoothened (Smo). In Drosophila, protein kinase A (PKA) phosphorylates and activates Smo in cells stimulated with Hh. In unstimulated cells, PKA phosphorylates and inhibits the transcription factor Cubitus interruptus (Ci). We found that in cells exposed to Hh, the catalytic subunit of PKA (PKAc) bound to the juxtamembrane region of the carboxyl terminus of Smo. PKA-mediated phosphorylation of Smo further enhanced its association with PKAc to form stable kinase-substrate complexes that promoted the PKA-mediated transphosphorylation of Smo dimers. We identified multiple basic residues in the carboxyl terminus of Smo that were required for interaction with PKAc, Smo phosphorylation, and Hh pathway activation. Hh induced a switch from the association of PKAc with a cytosolic complex of Ci and the kinesin-like protein Costal2 (Cos2) to a membrane-bound Smo-Cos2 complex. Thus, our study uncovers a previously uncharacterized mechanism for regulation of PKA activity and demonstrates that the signal-regulated formation of kinase-substrate complexes plays a central role in Hh signal transduction.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

Summary

Fig. S1. Hh signaling stabilizes PKAc depending on Smo C-tail.
Fig. S2. Characterization of AKAR3 and Myr-AKAR3 in S2 cells.
Fig. S3. Hh increases Myr-AKAR3 FRET in S2 cells.
Fig. S4. Hh signaling increases Myr-AKAR3 FRET in wing discs.
Fig. S5. Characterization of PKAc-Smo interaction by coimmunoprecipitation assay.
Fig. S6. Multiple basic clusters mediate binding of PKAc to the SAID domain.
Fig. S7. Hh induces colocalization between mC* and truncated Smo independent of endogenous Smo.
Fig. S8. Hh induces FRET between CFP-tagged Smo variants and mC*-YFP.
Fig. S9. Characterization of Smo expression driven by different Gal4 drivers.
Fig. S10. Smo-PKAc complex formation stabilizes PKAc.
Fig. S11. Hh switches the binding of PKAc from Cos2 to Smo.

Resources

File (7_ra62_sm.pdf)

REFERENCES AND NOTES

1
Jiang J., Hui C. C., Hedgehog signaling in development and cancer. Dev. Cell 15, 801–812 (2008).
2
Ingham P. W., Nakano Y., Seger C., Mechanisms and functions of Hedgehog signalling across the metazoa. Nat. Rev. Genet. 12, 393–406 (2011).
3
Taipale J., Beachy P. A., The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).
4
Briscoe J., Thérond P. P., The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14, 416–429 (2013).
5
Wilson C. W., Chuang P. T., Mechanism and evolution of cytosolic Hedgehog signal transduction. Development 137, 2079–2094 (2010).
6
Robbins D. J., Fei D. L., Riobo N. A., The Hedgehog signal transduction network. Sci. Signal. 5, re6 (2012).
7
Ingham P. W., Segment polarity genes and cell patterning within the Drosophila body segment. Curr. Opin. Genet. Dev. 1, 261–267 (1991).
8
Taipale J., Cooper M. K., Maiti T., Beachy P. A., Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892–897 (2002).
9
Stone D. M., Hynes M., Armanini M., Swanson T. A., Gu Q., Johnson R. L., Scott M. P., Pennica D., Goddard A., Phillips H., Noll M., Hooper J. E., de Sauvage F., Rosenthal A., The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384, 129–134 (1996).
10
Casali A., Struhl G., Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Nature 431, 76–80 (2004).
11
Chen Y., Jiang J., Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res. 23, 186–200 (2013).
12
Denef N., Neubüser D., Perez L., Cohen S. M., Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell 102, 521–531 (2000).
13
Jia J., Tong C., Wang B., Luo L., Jiang J., Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432, 1045–1050 (2004).
14
Corbit K. C., Aanstad P., Singla V., Norman A. R., Stainier D. Y., Reiter J. F., Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005).
15
Zhao Y., Tong C., Jiang J., Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450, 252–258 (2007).
16
Chen Y., Sasai N., Ma G., Yue T., Jia J., Briscoe J., Jiang J., Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLOS Biol. 9, e1001083 (2011).
17
Hui C. C., Angers S., Gli proteins in development and disease. Annu. Rev. Cell Dev. Biol. 27, 513–537 (2011).
18
Jiang J., Struhl G., Protein kinase A and hedgehog signaling in drosophila limb development. Cell 80, 563–572 (1995).
19
Li W., Ohlmeyer J. T., Lane M. E., Kalderon D., Function of protein kinase A in hedgehog signal transduction and Drosophila imaginal disc development. Cell 80, 553–562 (1995).
20
Pan D., Rubin G. M., cAMP-dependent protein kinase and hedgehog act antagonistically in regulating decapentaplegic transcription in drosophila imaginal discs. Cell 80, 543–552 (1995).
21
Tuson M., He M., Anderson K. V., Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138, 4921–4930 (2011).
22
Jiang J., Struhl G., Regulation of the Hedgehog and Wingless signalling pathways by the F- box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).
23
Jia J., Amanai K., Wang G., Tang J., Wang B., Jiang J., Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416, 548–552 (2002).
24
Jia J., Zhang L., Zhang Q., Tong C., Wang B., Hou F., Amanai K., Jiang J., Phosphorylation by double-time/CKIε and CKIα targets Cubitus interruptus for Slimb/β-TRCP-mediated proteolytic processing. Dev. Cell 9, 819–830 (2005).
25
Price M. A., Kalderon D., Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by glycogen synthase kinase 3 and casein kinase 1. Cell 108, 823–835 (2002).
26
Smelkinson M. G., Zhou Q., Kalderon D., Regulation of Ci-SCFSlimb binding, Ci proteolysis, and Hedgehog pathway activity by Ci phosphorylation. Dev. Cell 13, 481–495 (2007).
27
Tempé D., Casas M., Karaz S., Blanchet-Tournier M. F., Concordet J. P., Multisite protein kinase A and glycogen synthase kinase 3β phosphorylation leads to Gli3 ubiquitination by SCFβTrCP. Mol. Cell. Biol. 26, 4316–4326 (2006).
28
Wang B., Li Y., Evidence for the direct involvement of βTrCP in Gli3 protein processing. Proc. Natl. Acad. Sci. U.S.A. 103, 33–38 (2006).
29
Aza-Blanc P., Ramírez-Weber F., Laget M., Schwartz C., Kornberg T., Proteolysis that is inhibited by Hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89, 1043–1053 (1997).
30
Zhang W., Zhao Y., Tong C., Wang G., Wang B., Jia J., Jiang J., Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev. Cell 8, 267–278 (2005).
31
Wang B., Fallon J. F., Beachy P. A., Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000).
32
Fan J., Liu Y., Jia J., Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner. Dev. Biol. 366, 172–184 (2012).
33
Zhang C., Williams E. H., Guo Y., Lum L., Beachy P. A., Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc. Natl. Acad. Sci. U.S.A. 101, 17900–17907 (2004).
34
Apionishev S., Katanayeva N. M., Marks S. A., Kalderon D., Tomlinson A., Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nat. Cell Biol. 7, 86–92 (2005).
35
Chen Y., Li S., Tong C., Zhao Y., Wang B., Liu Y., Jia J., Jiang J., G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila. Genes Dev. 24, 2054–2067 (2010).
36
Wang G., Amanai K., Wang B., Jiang J., Interactions with Costal2 and Suppressor of Fused regulate nuclear translocation and activity of Cubitus interruptus. Genes Dev. 14, 2893–2905 (2000).
37
Cheung H. O., Zhang X., Ribeiro A., Mo R., Makino S., Puviindran V., Law K. K., Briscoe J., Hui C. C., The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian Hedgehog signaling. Sci. Signal. 2, ra29 (2009).
38
Endoh-Yamagami S., Evangelista M., Wilson D., Wen X., Theunissen J. W., Phamluong K., Davis M., Scales S. J., Solloway M. J., de Sauvage F. J., Peterson A. S., The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr. Biol. 19, 1320–1326 (2009).
39
Liem K. F., He M., Ocbina P. J., Anderson K. V., Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling. Proc. Natl. Acad. Sci. U.S.A. 106, 13377–13382 (2009).
40
Maurya A. K., Ben J., Zhao Z., Lee R. T., Niah W., Ng A. S., Iyu A., Yu W., Elworthy S., van Eeden F. J., Ingham P. W., Positive and negative regulation of Gli activity by Kif7 in the zebrafish embryo. PLOS Genet. 9, e1003955 (2013).
41
Shi Q., Li S., Jia J., Jiang J., The Hedgehog-induced Smoothened conformational switch assembles a signaling complex that activates Fused by promoting its dimerization and phosphorylation. Development 138, 4219–4231 (2011).
42
Yang C., Chen W., Chen Y., Jiang J., Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell Res. 22, 1593–1604 (2012).
43
Taylor S. S., Buechler J. A., Yonemoto W., cAMP-dependent protein kinase: Framework for a diverse family of regulatory enzymes. Annu. Rev. Biochem. 59, 971–1005 (1990).
44
Ogden S. K., Fei D. L., Schilling N. S., Ahmed Y. F., Hwa J., Robbins D. J., G protein Gαi functions immediately downstream of Smoothened in Hedgehog signalling. Nature 456, 967–970 (2008).
45
Jia H., Liu Y., Yan W., Jia J., PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation. Development 136, 307–316 (2009).
46
Su Y., Ospina J. K., Zhang J., Michelson A. P., Schoen A. M., Zhu A. J., Sequential phosphorylation of Smoothened transduces graded Hedgehog signaling. Sci. Signal. 4, ra43 (2011).
47
Basler K., Struhl G., Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368, 208–214 (1994).
48
Tabata T., Kornberg T. B., Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76, 89–102 (1994).
49
Nakano Y., Guerrero I., Hidalgo A., Taylor A., Whittle J. R., Ingham P. W., A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched. Nature 341, 508–513 (1989).
50
Zhang J., Hupfeld C. J., Taylor S. S., Olefsky J. M., Tsien R. Y., Insulin disrupts β-adrenergic signalling to protein kinase A in adipocytes. Nature 437, 569–573 (2005).
51
Allen M. D., Zhang J., Subcellular dynamics of protein kinase A activity visualized by FRET-based reporters. Biochem. Biophys. Res. Commun. 348, 716–721 (2006).
52
Seamon K. B., Padgett W., Daly J. W., Forskolin: Unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc. Natl. Acad. Sci. U.S.A. 78, 3363–3367 (1981).
53
Lum L., Zhang C., Oh S., Mann R. K., von Kessler D. P., Taipale J., Weis-Garcia F., Gong R., Wang B., Beachy P. A., Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2. Mol. Cell 12, 1261–1274 (2003).
54
Wang G., Wang B., Jiang J., Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes Dev. 13, 2828–2837 (1999).
55
Chen Y., Struhl G., In vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Development 125, 4943–4948 (1998).
56
Li S., Chen Y., Shi Q., Yue T., Wang B., Jiang J., Hedgehog-regulated ubiquitination controls Smoothened trafficking and cell surface expression in Drosophila. PLOS Biol. 10, e1001239 (2012).
57
Lum L., Yao S., Mozer B., Rovescalli A., Von Kessler D., Nirenberg M., Beachy P. A., Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299, 2039–2045 (2003).
58
Knighton D. R., Zheng J. H., Ten Eyck L. F., Xuong N. H., Taylor S. S., Sowadski J. M., Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253, 414–420 (1991).
59
Centonze V. E., Sun M., Masuda A., Gerritsen H., Herman B., Fluorescence resonance energy transfer imaging microscopy. Methods Enzymol. 360, 542–560 (2003).
60
Shi D., Lv X., Zhang Z., Yang X., Zhou Z., Zhang L., Zhao Y., Smoothened oligomerization/higher order clustering in lipid rafts is essential for high Hedgehog activity transduction. J. Biol. Chem. 288, 12605–12614 (2013).
61
Ruel L., Rodriguez R., Gallet A., Lavenant-Staccini L., Thérond P. P., Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Nat. Cell Biol. 5, 907–913 (2003).
62
Jia J., Tong C., Jiang J., Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail. Genes Dev. 17, 2709–2720 (2003).
63
Ogden S. K., Ascano M., Stegman M. A., Suber L. M., Hooper J. E., Robbins D. J., Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr. Biol. 13, 1998–2003 (2003).
64
Strigini M., Cohen S. M., A Hedgehog activity gradient contributes to AP axial patterning of the Drosophila wing. Development 124, 4697–4705 (1997).
65
Chen Y., Struhl G., Dual roles for Patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).
66
Ohlmeyer J. T., Kalderon D., Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator. Nature 396, 749–753 (1998).
67
DeCamp D. L., Thompson T. M., de Sauvage F. J., Lerner M. R., Smoothened activates Gαi-mediated signaling in frog melanophores. J. Biol. Chem. 275, 26322–26327 (2000).
68
Riobo N. A., Saucy B., Dilizio C., Manning D. R., Activation of heterotrimeric G proteins by Smoothened. Proc. Natl. Acad. Sci. U.S.A. 103, 12607–12612 (2006).
69
Mukhopadhyay S., Wen X., Ratti N., Loktev A., Rangell L., Scales S. J., Jackson P. K., The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 152, 210–223 (2013).
70
Regard J. B., Malhotra D., Gvozdenovic-Jeremic J., Josey M., Chen M., Weinstein L. S., Lu J., Shore E. M., Kaplan F. S., Yang Y., Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat. Med. 19, 1505–1512 (2013).
71
Cheng S., Maier D., Hipfner D. R., Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling. Development 139, 85–94 (2012).
72
Wong W., Scott J. D., AKAP signalling complexes: Focal points in space and time. Nat. Rev. Mol. Cell Biol. 5, 959–970 (2004).
73
Barzi M., Berenguer J., Menendez A., Alvarez-Rodriguez R., Pons S., Sonic-hedgehog-mediated proliferation requires the localization of PKA to the cilium base. J. Cell Sci. 123, 62–69 (2010).
74
Huangfu D., Anderson K. V., Signaling from Smo to Ci/Gli: Conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133, 3–14 (2006).
75
Taylor S. S., Knighton D. R., Zheng J., Ten Eyck L. F., Sowadski J. M., Structural framework for the protein kinase family. Annu. Rev. Cell Biol. 8, 429–462 (1992).
76
Calleja M., Moreno E., Pelaz S., Morata G., Visualization of gene expression in living adult Drosophila. Science 274, 252–255 (1996).
77
Lee T., Luo L., Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci. 24, 251–254 (2001).
78
Cross F. R., Garber E. A., Pellman D., Hanafusa H., A short sequence in the p60src N terminus is required for p60src myristylation and membrane association and for cell transformation. Mol. Cell. Biol. 4, 1834–1842 (1984).
79
Simon M. A., Drees B., Kornberg T., Bishop J. M., The nucleotide sequence and the tissue-specific expression of Drosophila c-src. Cell 42, 831–840 (1985).
80
Iyer G. H., Moore M. J., Taylor S. S., Consequences of lysine 72 mutation on the phosphorylation and activation state of cAMP-dependent kinase. J. Biol. Chem. 280, 8800–8807 (2005).
81
Peters J. M., McKay R. M., McKay J. P., Graff J. M., Casein kinase I transduces Wnt signals. Nature 401, 345–350 (1999).
82
Bischof J., Maeda R. K., Hediger M., Karch F., Basler K., An optimized transgenesis system for Drosophila using germ-line-specific ϕC31 integrases. Proc. Natl. Acad. Sci. U.S.A. 104, 3312–3317 (2007).
83
Liu Y., Cao X., Jiang J., Jia J., Fused–Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation. Genes Dev. 21, 1949–1963 (2007).
84
Rubin G. M., Spradling A. C., Genetic transformation of Drosophila with transposable element vectors. Science 218, 348–353 (1982).
85
Motzny C. K., Holmgren R., The Drosophila cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways. Mech. Dev. 52, 137–150 (1995).
86
Chen C. H., von Kessler D. P., Park W., Wang B., Ma Y., Beachy P. A., Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell 98, 305–316 (1999).
87
Nybakken K., Vokes S. A., Lin T. Y., McMahon A. P., Perrimon N., A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. Nat. Genet. 37, 1323–1332 (2005).

(0)eLetters

eLetters is an online forum for ongoing peer review. Submission of eLetters are open to all. eLetters are not edited, proofread, or indexed. Please read our Terms of Service before submitting your own eLetter.

Log In to Submit a Response

No eLetters have been published for this article yet.

Information & Authors

Information

Published In

Science Signaling
Volume 7 | Issue 332
July 2014

Submission history

Received: 24 April 2014
Accepted: 11 June 2014

Permissions

Request permissions for this article.

Acknowledgments

We thank J. Jia, J. Zhang, Y. Zhao, R. Holmgren, G. Struhl, DSHB, and Bloomington Stock Centers for fly stocks and reagents. Funding: This work is supported by grants from the NIH (GM061269 and GM067045), National Natural Science Foundation of China (31328017), and Welch Foundation (I-1603). J.J. is a Eugene McDermott Endowed Scholar in Biomedical Science at University of Texas Southwestern Medical Center. Author contributions: S.L. and J.J. designed the experiments; S.L., G.M., and B.W. performed the experiments; S.L., G.M., and J.J. analyzed the data; and S.L. and J.J. wrote the manuscript. Competing interests: The authors declare that they have no competing interests.

Authors

Affiliations

Shuang Li*
Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Guoqiang Ma*
Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Bing Wang
Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

Notes

*
These authors contributed equally to this work.
Corresponding author. E-mail: [email protected]

Metrics & Citations

Metrics

Article Usage
Altmetrics

Citations

Export citation

Select the format you want to export the citation of this publication.

Cited by

  1. Characterization of Smoothened Phosphorylation and Activation, Hedgehog Signaling, (121-137), (2022).https://doi.org/10.1007/978-1-0716-1701-4_11
    Crossref
  2. Cell-Based Assays for Smoothened Ubiquitination and Sumoylation, Hedgehog Signaling, (139-147), (2022).https://doi.org/10.1007/978-1-0716-1701-4_12
    Crossref
  3. Hedgehog signaling mechanism and role in cancer, Seminars in Cancer Biology, (2021).https://doi.org/10.1016/j.semcancer.2021.04.003
    Crossref
  4. Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases, Science Signaling, 11, 516, (2021)./doi/10.1126/scisignal.aan8660
    Abstract
  5. Mechanisms of Smoothened Regulation in Hedgehog Signaling, Cells, 10, 8, (2138), (2021).https://doi.org/10.3390/cells10082138
    Crossref
  6. Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium, Science China Life Sciences, (2021).https://doi.org/10.1007/s11427-021-1975-9
    Crossref
  7. Structural insight into the recognition between Sufu and fused in the Hedgehog signal transduction pathway, Journal of Structural Biology, 212, 2, (107614), (2020).https://doi.org/10.1016/j.jsb.2020.107614
    Crossref
  8. Sterols in an intramolecular channel of Smoothened mediate Hedgehog signaling, Nature Chemical Biology, 16, 12, (1368-1375), (2020).https://doi.org/10.1038/s41589-020-0646-2
    Crossref
  9. Mechanistic Insights into the Generation and Transduction of Hedgehog Signaling, Trends in Biochemical Sciences, 45, 5, (397-410), (2020).https://doi.org/10.1016/j.tibs.2020.01.006
    Crossref
  10. Drosophila hedgehog can act as a morphogen in the absence of regulated Ci processing, eLife, 9, (2020).https://doi.org/10.7554/eLife.61083
    Crossref
Loading...

View Options

Check Access

Log in to view the full text

AAAS ID LOGIN

AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Log in via OpenAthens.
Log in via Shibboleth.

More options

Register for free to read this article

As a service to the community, this article is available for free. Login or register for free to read this article.

View options

PDF format

Download this article as a PDF file

Download PDF

Full Text

FULL TEXT

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media