Key Points
-
Complex organisms rely on a small number of signalling pathways to regulate all of their responses to developmental and environmental cues. These pathways achieve considerable levels of diversity and selectivity through extensive integration and crosstalk.
-
In addition to being small in number, many components of signalling pathways are shared among multiple systems. This creates the need for mechanisms to allow the insulation of signals and discrimination of outcomes.
-
Using the Wnt and Hippo signalling pathways as examples, there are multiple mechanisms whereby pathways influence each other yet retain their own specificity. Through feedback loops, pathway duration and intensity is often tightly controlled. Loss of such controls can lead to chronic signalling and various diseases.
-
Species conservation of the key regulatory pathways is extensive, allowing extrapolation of overall topologies. However, rigorous genetic analysis of Drosophila melanogaster and nematodes has also revealed that interactions are often indirect and has uncovered distinct functions of many components.
-
The fact that more than one pathway may share a common protein does not mean that these proteins are common nodes of signal transduction between the pathways. Indeed, this is typically not the case because of sequestration of molecules through scaffolds and complexes. However, the use of chemical inhibitors or RNA interference to common components breaks down these natural barriers.
-
Building signalling systems on several common elements probably does provide a fundamental level of coordination by allowing the re-balancing of multiple pathways should one important component become limiting.
Abstract
Signal transduction pathways interact at various levels to define tissue morphology, size and differentiation during development. Understanding the mechanisms by which these pathways collude has been greatly enhanced by recent insights into how shared components are independently regulated and how the activity of one system is contextualized by others. Traditionally, it has been assumed that the components of signalling pathways show pathway fidelity and act with a high degree of autonomy. However, as illustrated by the Wnt and Hippo pathways, there is increasing evidence that components are often shared between multiple pathways and other components talk to each other through multiple mechanisms.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cohen, P. The role of protein phosphorylation in neural and hormonal control of cellular activity. Nature 296, 613–620 (1982).
van Amerongen, R. & Nusse, R. Towards an integrated view of Wnt signaling in development. Development 136, 3205–3214 (2009).
MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009). References 2 and 3 provide excellent and up-to-date reviews of Wnt signalling.
Zhao, B., Lei, Q. Y. & Guan, K. L. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr. Opin. Cell Biol. 20, 638–646 (2008).
Zeng, Q. & Hong, W. The emerging role of the Hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell 13, 188–192 (2008). References 4 and 5 provide excellent and up-to-date reviews of Hippo signalling.
Klingensmith, J. & Nusse, R. Signaling by Wingless in Drosophila. Dev. Biol. 166, 396–414 (1994).
Major, M. B. et al. Wilms tumor suppressor WTX negatively regulates WNT/β-catenin signaling. Science 316, 1043–1046 (2007).
Miller, B. W. et al. Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway. Mol. Syst. Biol. 5, 315 (2009). References 7 and 8 provide excellent examples of the power of proteomic approaches for the unbiased assessment of pathway topology and interactions.
Mosimann, C., Hausmann, G. & Basler, K. β-catenin hits chromatin: regulation of Wnt target gene activation. Nature Rev. Mol. Cell Biol. 10, 276–286 (2009).
Jho, E. H. et al. Wnt/β-catenin/TCF signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol. Cell. Biol. 22, 1172–1183 (2002).
Lee, E., Salic, A., Kruger, R., Heinrich, R. & Kirschner, M. W. The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. 1, E10 (2003).
Benchabane, H., Hughes, E. G., Takacs, C. M., Baird, J. R. & Ahmed, Y. Adenomatous polyposis coli is present near the minimal level required for accurate graded responses to the Wingless morphogen. Development 135, 963–971 (2008).
Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 17, 45–51 (2007).
Doble, B. W., Patel, S., Wood, G. A., Kockeritz, L. K. & Woodgett, J. R. Functional redundancy of GSK-3α and GSK-3β in Wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev. Cell 12, 957–971 (2007). Describes the insensitivity to the loss of GSK3 alleles in embryonic stem cells and reveals a requirement for GSK3 in differentiation.
Cohen, P. & Frame, S. The renaissance of GSK3. Nature Rev. Mol. Cell Biol. 2, 769–776 (2001).
Davidson, G. et al. Casein kinase 1γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867–872 (2005).
Zeng, X. et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438, 873–877 (2005).
Zeng, X. et al. Initiation of Wnt signaling: control of Wnt coreceptor LRP6 phosphorylation/activation via Frizzled, Dishevelled and Axin functions. Development 135, 367–375 (2008). References 16–18 describe the positive roles of two protein kinases in Wnt signalling that had previously been ascribed negative functions.
Takacs, C. M. et al. Dual positive and negative regulation of Wingless signaling by Adenomatous polyposis coli. Science 319, 333–336 (2008).
McManus, E. J. et al. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 24, 1571–1583 (2005).
Ng, S. S. et al. Phosphatidylinositol 3-kinase signaling does not activate the Wnt cascade. J. Biol. Chem. 284, 35308–35313 (2009). Provides compelling evidence to debunk the link between PI3K signals and Wnt responses, demonstrating signal authenticity.
Orsulic, S. & Peifer, M. An in vivo structure-function study of Armadillo, the β-catenin homologue, reveals both separate and overlapping regions of the protein required for cell adhesion and for Wingless signaling. J. Cell Biol. 134, 1283–300 (1996).
Simons, M. & Mlodzik, M. Planar cell polarity signaling: from fly development to human disease. Annu. Rev. Genet. 42, 517–540 (2008).
Chen, W. S. et al. Asymmetric homotypic interactions of the atypical cadherin Flamingo mediate intercellular polarity signaling. Cell 133, 1093–1105 (2008).
Lawrence, P. A., Casal, J. & Struhl, G. Towards a model of the organisation of planar polarity and pattern in the Drosophila abdomen. Development 129, 2749–2760 (2002).
Casal, J., Struhl, G. & Lawrence, P. A. Developmental compartments and planar polarity in Drosophila. Curr. Biol. 12, 1189–1198 (2002).
Rawls, A. S., Guinto, J. B. & Wolff, T. The cadherins Fat and Dachsous regulate dorsal/ventral signaling in the Drosophila eye. Curr. Biol. 12, 1021–1026 (2002).
Yang, C. H., Axelrod, J. D. & Simon, M. A. Regulation of Frizzled by Fat-like cadherins during planar polarity signaling in the Drosophila compound eye. Cell 108, 675–688 (2002).
Saburi, S. et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nature Genet. 40, 1010–1015 (2008). Provides evidence for conserved roles of D. melanogaster Fat and mammalian FAT4 in PCP pathways.
Casal, J., Lawrence, P. A. & Struhl, G. Two separate molecular systems, Dachsous/Fat and Starry night/Frizzled, act independently to confer planar cell polarity. Development 133, 4561–4572 (2006).
Sopko, R. & McNeill, H. The skinny on Fat: an enormous cadherin that regulates cell adhesion, tissue growth, and planar cell polarity. Curr. Opin. Cell Biol. 21, 717–723 (2009).
Fanto, M. et al. The tumor-suppressor and cell adhesion molecule Fat controls planar polarity via physical interactions with Atrophin, a transcriptional co-repressor. Development 130, 763–774 (2003).
Matakatsu, H. & Blair, S. S. Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131, 3785–3794 (2004).
Simon, M. A. Planar cell polarity in the Drosophila eye is directed by graded Four-jointed and Dachsous expression. Development 131, 6175–6184 (2004).
Yin, C., Ciruna, B. & Solnica-Krezel, L. Convergence and extension movements during vertebrate gastrulation. Curr. Top. Dev. Biol. 89, 163–192 (2009).
Du, S. J., Purcell, S. M., Christian, J. L., McGrew, L. L. & Moon, R. T. Identification of distinct classes and functional domains of Wnts through expression of wild-type and chimeric proteins in Xenopus embryos. Mol. Cell. Biol. 15, 2625–2634 (1995). This analysis provides an effective classification schema and structure–function analysis of the Wnt family of ligands.
Wong, G. T., Gavin, B. J. & McMahon, A. P. Differential transformation of mammary epithelial cells by Wnt genes. Mol. Cell. Biol. 14, 6278–6286 (1994).
Angers, S. & Moon, R. T. Proximal events in Wnt signal transduction. Nature Rev. Mol. Cell Biol. 10, 468–477 (2009).
Torres, M. A. et al. Activities of the Wnt-1 class of secreted signaling factors are antagonized by the Wnt-5A class and by a dominant negative cadherin in early Xenopus development. J. Cell Biol. 133, 1123–37 (1996).
Ishitani, T. et al. The TAK1-NLK-MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF. Nature 399, 798–802 (1999).
Meneghini, M. D. et al. MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans. Nature 399, 793–797 (1999).
Rousset, R. et al. Naked cuticle targets Dishevelled to antagonize Wnt signal transduction. Genes Dev. 15, 658–671 (2001).
Yan, D. et al. Cell autonomous regulation of multiple Dishevelled-dependent pathways by mammalian Nkd. Proc. Natl Acad. Sci. USA 98, 3802–3807 (2001).
Lee, J. M. et al. RORα attenuates Wnt/β-catenin signaling by PKCα-dependent phosphorylation in colon cancer. Mol. Cell 37, 183–195 (2010).
Minami, Y., Oishi, I., Endo, M. & Nishita, M. Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases. Dev. Dyn. 239, 1–15 (2010).
Sato, A., Yamamoto, H., Sakane, H., Koyama, H. & Kikuchi, A. Wnt5a regulates distinct signalling pathways by binding to Frizzled2. EMBO J. 29, 41–54 (2010).
Matsumoto, S., Fumoto, K., Okamoto, T., Kaibuchi, K. & Kikuchi, A. Binding of APC and dishevelled mediates Wnt5a-regulated focal adhesion dynamics in migrating cells. EMBO J. 29, 1192–1204 (2010).
Rusan, N. M. & Peifer, M. Original CIN: reviewing roles for APC in chromosome instability. J. Cell Biol. 181, 719–726 (2008).
O'Connell, M. P. et al. The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma. Oncogene 29, 34–44 (2010).
Roman-Gomez, J. et al. WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia. Eur. J. Cancer 43, 2736–46 (2007).
Oishi, I. et al. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8, 645–654 (2003).
Mikels, A. J. & Nusse, R. Purified Wnt5a protein activates or inhibits β-catenin-TCF signaling depending on receptor context. PLoS Biol. 4, e115 (2006).
He, X. et al. A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 275, 1652–4 (1997).
Green, J. L., Kuntz, S. G. & Sternberg, P. W. Ror receptor tyrosine kinases: orphans no more. Trends Cell Biol. 18, 536–544 (2008).
Yamamoto, S. et al. Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev. Cell 15, 23–36 (2008).
Clevers, H. Wnt signaling: Ig-norrin the dogma. Curr. Biol. 14, R436–R437 (2004).
Badouel, C. et al. The FERM-domain protein Expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie. Dev. Cell 16, 411–420 (2009).
Goulev, Y. et al. Scalloped interacts with Yorkie, the nuclear effector of the Hippo tumor-suppressor pathway in Drosophila. Curr. Biol. 18, 435–441 (2008).
Wu, S., Liu, Y., Zheng, Y., Dong, J. & Pan, D. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev. Cell 14, 388–398 (2008).
Zhang, L. et al. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev. Cell 14, 377–387 (2008).
Bennett, F. C. & Harvey, K. F. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr. Biol. 16, 2101–2110 (2006).
Cho, E. et al. Delineation of a Fat tumor suppressor pathway. Nature Genet. 38, 1142–1150 (2006).
Silva, E., Tsatskis, Y., Gardano, L., Tapon, N. & McNeill, H. The tumor-suppressor gene fat controls tissue growth upstream of Expanded in the Hippo signaling pathway. Curr. Biol. 16, 2081–2089 (2006).
Willecke, M. et al. The Fat cadherin acts through the Hippo tumor-suppressor pathway to regulate tissue size. Curr. Biol. 16, 2090–2100 (2006). References 62–64 position and characterize the key molecules associated with Fat signalling into a pathway.
Yu, J., Poulton, J., Huang, Y. C. & Deng, W. M. The Hippo pathway promotes Notch signaling in regulation of cell differentiation, proliferation, and oocyte polarity. PLoS One 3, e1761 (2008).
Meignin, C., Alvarez-Garcia, I., Davis, I. & Palacios, I. M. The Salvador-Warts-Hippo pathway is required for epithelial proliferation and axis specification in Drosophila. Curr. Biol. 17, 1871–1878 (2007).
Polesello, C. & Tapon, N. Salvador-Warts-Hippo signaling promotes Drosophila posterior follicle cell maturation downstream of Notch. Curr. Biol. 17, 1864–1870 (2007).
Hamaratoglu, F. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nature Cell Biol. 8, 27–36 (2006).
Sopko, R. et al. Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase Discs overgrown. Curr. Biol. 19, 1112–1117 (2009).
Feng, Y. & Irvine, K. D. Processing and phosphorylation of the Fat receptor. Proc. Natl Acad. Sci. USA 106, 11989–11994 (2009).
Yu, J. et al. Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev. Cell 18, 288–299 (2010).
Baumgartner, R., Poernbacher, I., Buser, N., Hafen, E. & Stocker, H. The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev. Cell 18, 309–316 (2010).
Genevet, A., Wehr, M. C., Brain, R., Thompson, B. J. & Tapon, N. Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev. Cell 18, 300–308 (2010).
Oh, H., Reddy, B. V. & Irvine, K. D. Phosphorylation-independent repression of Yorkie in Fat-Hippo signaling. Dev. Biol. 335, 188–197 (2009).
Rogulja, D., Rauskolb, C. & Irvine, K. D. Morphogen control of wing growth through the Fat signaling pathway. Dev. Cell 15, 309–321 (2008).
Baena-Lopez, L. A., Rodriguez, I. & Baonza, A. The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating Dally and Dally-like. Proc. Natl Acad. Sci. USA 105, 9645–9650 (2008).
Herranz, H. & Milan, M. Signalling molecules, growth regulators and cell cycle control in Drosophila. Cell Cycle 7, 3335–3337 (2008).
Peng, H. W., Slattery, M. & Mann, R. S. Transcription factor choice in the Hippo signaling pathway: Homothorax and Yorkie regulation of the microRNA bantam in the progenitor domain of the Drosophila eye imaginal disc. Genes Dev. 23, 2307–2319 (2009).
Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139, 757–769 (2009).
Fernandez, L. A. et al. YAP1 is amplified and up-regulated in Hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 23, 2729–2741 (2009).
Varelas, X. et al. The Hippo pathway regulates Wnt/β-catenin signalling. Dev. Cell 18, 579–591 (2010).
Yuan, Z. et al. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J. Biol. Chem. 285, 3815–3824 (2010).
Zhang, J. et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nature Cell Biol. 11, 1444–1450 (2009).
Zhou, D. et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).
Owens, D. M. & Keyse, S. M. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203–3213 (2007).
Huang, S. M. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009). Reveals a new level of regulation of Wnt signalling through the tankyrase-mediated destabilization of axin 1.
Albeck, J. G. et al. Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol. Cell 30, 11–25 (2008).
Arnold, H. K. et al. The Axin1 scaffold protein promotes formation of a degradation complex for c-Myc. EMBO J. 28, 500–512 (2009).
Goentoro, L. & Kirschner, M. W. Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling. Mol. Cell 36, 872–884 (2009).
Buchert, M. et al. Genetic dissection of differential signaling threshold requirements for the Wnt/β-catenin pathway in vivo. PLoS Genet. 6, e1000816 (2010).
Yokota, Y. et al. The adenomatous polyposis coli protein is an essential regulator of radial glial polarity and construction of the cerebral cortex. Neuron 61, 42–56 (2009).
Goentoro, L., Shoval, O., Kirschner, M. W. & Alon, U. The incoherent feedforward loop can provide fold-change detection in gene regulation. Mol. Cell 36, 894–899 (2009).
Kim, W. Y. et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nature Neurosci. 12, 1390–1397 (2009).
Acknowledgements
The authors acknowledge support from the Canadian Institutes of Health Research.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Related links
FURTHER INFORMATION
Glossary
- Cadherin
-
One of a family of transmembrane proteins that form homotypic, Ca2+-dependent interactions between cells, promoting adhesion.
- GPCR
-
A type of receptor protein that traverses the membrane seven times and is typically coupled to G proteins (also known as Serpentine receptors).
- Planar cell polarity
-
A mechanism of cellular organization, distinct from apical–basal polarity, that is important in providing a higher order of arrangements in flat sheets of epithelial cells.
- Convergent extension
-
A non-mitotic developmental process that involves elongation in one axis of a band (or bands) of cells, usually resulting in the coverage of a structure.
- Neural tube
-
The precursor structure of the vertebrate nervous system that develops into the brain and spinal cord.
- CRD domain
-
A Cys-rich region located on the extracellular portion of GPCR receptors that is essential for binding ligands.
- WW repeat
-
A protein motif that binds certain polyPro peptides and/or phosphorylated peptides (usually phosphoSer or phosphoThr peptides).
- Contact inhibition
-
The growth-suppressive effect that occurs when epithelial cells are in physical contact.
- ADP ribosylation
-
A post-translational modification involving the transfer of an ADP ribose moiety from nicotinamide adenine dinucleotide to Arg, Glu or Asp acid side chains.
Rights and permissions
About this article
Cite this article
McNeill, H., Woodgett, J. When pathways collide: collaboration and connivance among signalling proteins in development. Nat Rev Mol Cell Biol 11, 404–413 (2010). https://doi.org/10.1038/nrm2902
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm2902
This article is cited by
-
Cytoskeleton-associated protein 4 (CKAP4) promotes malignant progression of human gliomas through inhibition of the Hippo signaling pathway
Journal of Neuro-Oncology (2021)
-
Pathway information extracted from 25 years of pathway figures
Genome Biology (2020)
-
Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy
BMC Medicine (2020)
-
CD146, from a melanoma cell adhesion molecule to a signaling receptor
Signal Transduction and Targeted Therapy (2020)
-
YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity
Nature Communications (2020)