Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb

Article metrics

Abstract

Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development1,2. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci)3,4, whereas Wg signal transduction causes increased stability of Armadillo (Arm/β-catenin)5, a possible co-factor for thetranscriptional regulator Lef1/TCF6. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh and Wg responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway7,8,9. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasomepathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Ectopic activity of the Hh signal transduction pathway in slmb1 mutant cells.
Figure 2: Accumulation of intact Ci protein in slmb1 mutant cells.
Figure 3: Ectopic activity of the Wg signal transduction pathway in slmbP1493 mutant cells.
Figure 4: slimb encodes an F-box/WD40-repeat protein related to Cdc4p and β-TRCP.

References

  1. 1

    Nusse, R. & Varmus, H. E. Wnt genes. Cell 69, 1073–1087 (1992).

  2. 2

    Ingham, P. W. Signaling by hedgehog family proteins in Drosophila and vertebrate development. Curr. Opin. Genet. Dev. 5, 492–498 (1995).

  3. 3

    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).

  4. 4

    Aza-Blanc, P., Ramirez-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).

  5. 5

    Miller, J. R. & Moon, RT. Signal transduction through β-catenin and specification of cell fate during embryogenesis. Genes Dev. 10, 2527–2539 (1996).

  6. 6

    Nusse, R. Aversatile transcriptional effector of wingless signaling. Cell 89, 321–323 (1997).

  7. 7

    Bai, C.et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86, 263–274 (1996).

  8. 8

    Feldman, R. M. R., Correll, C. C., Kaplan, K. B. & Deshaies, R. J. Acomplex of Cdc4p, Skp1p, and Cdc53p/Cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91, 221–230 (1997).

  9. 9

    Skowyra, D., Craig, K. L., Tyers, M., Elledge, S. J. & Harper, J. W. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91, 209–220 (1997).

  10. 10

    Jiang, J. & Struhl, G. Protein kinase A and Hedgehog signalling in Drosophila limb development. Cell 80, 563–572 (1995).

  11. 11

    Basler, K. & Struhl, G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 368, 208–214 (1994).

  12. 12

    Tabata, T. & Kornberg, T. B. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76, 89–102 (1994).

  13. 13

    Lecuit, T.et al. Two distinct mechanisms for long-range patterning by Decapentaplegic in the Drosophila wing. Nature 381, 387–393 (1996).

  14. 14

    Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a DPP morphogen gradient. Cell 85, 357–368 (1996).

  15. 15

    Zecca, M., Basler, K. & Struhl, G. Direct and long-range action of a wingless morphogen gradient. Cell 87, 833–844 (1996).

  16. 16

    Neumann, C. J. & Cohen, S. M. Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124, 871–880 (1997).

  17. 17

    Kalderon, D. Morphogenetic signalling. Responses to hedgehog. Curr. Biol. 5, 580–582 (1995).

  18. 18

    Zecca, M., Basler, K. & Struhl, G. Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing. Development 121, 2265–2278 (1995).

  19. 19

    Nusse, R. Patching up Hedgehog. Nature 384, 119–120 (1996).

  20. 20

    Ruiz i Altaba, A. Catching a Gli-mpse of Hedgehog. Cell 90, 193–196 (1997).

  21. 21

    Irvine, K. & Vogt, T. F. Dorsal-ventral signaling in limb development. Curr. Opin. Cell. Biol. 9, 867–876 (1997).

  22. 22

    Campuzano, S. & Modolell, J. Patterning of the Drosophila nervous system: the achaete-scute gene complex. Trends Genet. 8, 202–208 (1992).

  23. 23

    Kominami, K. & Toda, T. Fission yeast WD-repeat protein Pop1 regulates genome ploidy through ubiquitin-proteasome-mediated degradatin ofthe CDK inhibitor Rum1 and the S-phase initiator Cdc18. Genes Dev. 11, 1548–1560 (1997).

  24. 24

    Palombella, V. J., Rando, O. J., Goldberg, A. L. & Maniatis, T. The ubiquitin-proteasome pathway is required for processign the NF-κB1 precursor protein and the activation of NF-κB. Cell 78, 773–785 (1994).

  25. 25

    Spevak, W., Keiper, B. D., Stratowa, C. & Castanon, M. J. Saccharomyces cerevisiae cdc15 mutants arrested at a late stage in anaphase are rescued by Xenopus cDNAs encoding N-ras or a protein with beta-transducin repeats. Mol. Cell. Biol. 13, 4953–4966 (1993).

  26. 26

    Yost, C.et al. The axis-inducing activity, stability and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10, 1443–1454 (1996).

  27. 27

    Aberle, H., Bauer, A., Stappert, J., Kispert, A. & Kemler, R. β-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16, 3797–3804 (1997).

  28. 28

    Peifer, M. β-catenin as oncogene: The smoking gun. Science 275, 1752–1753 (1997).

  29. 29

    Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87, 553–563 (1996).

  30. 30

    Jiang, J. & Struhl, G. Complementary and mutually exclusive activities of decapentaplegic and wingless organize axial patterning during Drosophila leg development. Cell 86, 401–409 (1996).

Download references

Acknowledgements

We thank A. Adachi and Q. Zhou for technical assistance; W. Strapps for help with western analysis; S. Carroll, S. Cohen, R. Holmgren, M. Peifer, M. Hoffman, G. Panganiban and T.Kornberg for antibodies; the Bloomington stock centre for fly stocks; and I. Greenwald, T. Jessell, R.Mann and A. Tomlinson for discussion and comments on the manuscript. J.J. is an NIH postdoctoral trainee; G.S. is an investigator of the Howard Hughes Medical Institute.

Author information

Correspondence to Jin Jiang.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.