Hippo Signaling Pathway

Pathway Description:

Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. In addition, dysregulation of the Hippo pathway contributes to cancer development. Core to the Hippo pathway is a kinase cascade, wherein Mst1/2 (ortholog of Drosophila Hippo) kinases and SAV1 form a complex to phosphorylate and activate LATS1/2. LATS1/2 kinases in turn phosphorylate and inhibit the transcription co-activators YAP and TAZ, two major downstream effectors of the Hippo pathway. When dephosphorylated, YAP/TAZ translocate into the nucleus and interact with TEAD1-4 and other transcription factors to induce expression of genes that promote cell proliferation and inhibit apoptosis. The Hippo pathway is involved in cell contact inhibition, and its activity is regulated at multiple levels: Mst1/2 and LATS1/2 are regulated by upstream molecules such as Merlin, KIBRA, RASSFs, and Ajuba; 14-3-3, α-catenin, AMOT, and ZO-2 retain YAP/TAZ in the cytoplasm, adherens junctions, or tight junctions by binding; Mst1/2 and YAP/TAZ phosphorylation and activity are modulated by phosphatases; Lats1/2 and YAP/TAZ stability are regulated by protein ubiquitination; and LATS1/2 activity is also regulated by the cytoskeleton. Despite extensive study of the Hippo pathway in the past decade, the exact nature of extracellular signals and membrane receptors regulating the Hippo pathway remains elusive.

Selected Reviews:

Badouel C, McNeill H (2011) SnapShot: The hippo signaling pathway. Cell 145(3), 484–484.e1.

Genevet A, Tapon N (2011) The Hippo pathway and apico-basal cell polarity. Biochem. J. 436(2), 213–24.

O'Hayre M, Degese MS, Gutkind JS (2014) Novel insights into G protein and G protein-coupled receptor signaling in cancer. Curr. Opin. Cell Biol. 27, 126–35.

Pan D (2010) The hippo signaling pathway in development and cancer. Dev. Cell 19(4), 491–505.

Sudol M, Harvey KF (2010) Modularity in the Hippo signaling pathway. Trends Biochem. Sci. 35(11), 627–33.

Yu FX, Guan KL (2013) The Hippo pathway: regulators and regulations. Genes Dev. 27(4), 355–71.

Zhao B, Li L, Lei Q, Guan KL (2010) The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 24(9), 862–74.

Zhao B, Tumaneng K, Guan KL (2011) The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Biol. 13(8), 877–83.

We would like to thank Prof. Kun-Liang Guan, University of California, San Diego, CA for contributing to this diagram.

created November 2010 revised July 2014

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ESC Pluripotency and Differentiation Signaling Pathway - See more at: http://www.cellsignal.com/common/content/content.jsp?id=pathways-esc#sthash.NAZaqSUu.dpuf

Pathway Description:

Two distinguishing characteristics of embryonic stem cells (ESCs) are pluripotency and the ability to self-renew. These traits, which allow ESCs to grow into any cell type in.the adult body and divide continuously in the undifferentiated state, are regulated by a number of cell signaling pathways. In human ESCs (hESCs), the predominant signaling pathways involved in pluripotency and self-renewal are TGF-β, which signals through Smad2/3/4, and FGFR, which activates the MAPK and Akt pathways. The Wnt pathway also promotes pluripotency, although this may occur through a non-canonical mechanism involving a balance between the transcriptional activator, TCF1, and the repressor, TCF3. Signaling through these pathways supports the pluripotent state, which relies predominantly upon three key transcription factors: Oct-4, Sox2, and Nanog. These transcription factors activate gene expression of ESC-specific genes, regulate their own expression, suppress genes involved in differentiation, and also serve as hESCs markers. Other markers used to identify hESCs are the cell surface glycolipid SSEA3/4, and glycoproteins TRA-1-60 and TRA-1-81. In vitro, hESCs can be coaxed into derivatives of the three primary germ layers, endoderm, mesoderm, or ectoderm, as well as primordial germ cell-like cells. One of the primary signaling pathways responsible for this process is the BMP pathway, which uses Smad1/5/9 to promote differentiation by both inhibiting expression of Nanog, as well as activating the expression of differentiation-specific genes. Notch also plays a role in differentiation through the notch intracellular domain (NICD). As differentiation continues, cells from each primary germ layer further differentiate along lineage-specific pathways.

Selected Reviews:

Bilic J, Izpisua Belmonte JC (2012) Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells 30(1), 33–41.

Dalton S (2013) Signaling networks in human pluripotent stem cells. Curr. Opin. Cell Biol. 25(2), 241–6.

Guenther MG (2011) Transcriptional control of embryonic and induced pluripotent stem cells. Epigenomics 3(3), 323–43.

Jaenisch R, Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132(4), 567–82.

Ng HH, Surani MA (2011) The transcriptional and signalling networks of pluripotency. Nat. Cell Biol. 13(5), 490–6.

Pan G, Thomson JA (2007) Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 17(1), 42–9.

Welham MJ, Kingham E, Sanchez-Ripoll Y, Kumpfmueller B, Storm M, Bone H (2011) Controlling embryonic stem cell proliferation and pluripotency: the role of PI3K- and GSK-3-dependent signalling. Biochem. Soc. Trans. 39(2), 674–8.

Young RA (2011) Control of the embryonic stem cell state. Cell 144(6), 940–54.

We would like to thank Justin Brumbaugh and Prof. Konrad Hochedlinger, HHMI and MGH Cancer Center, Center for Regenerative Medicine, Harvard University, Cambridge, MA, for reviewing this diagram.

created May 2009 revised Jully 2014

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Wnt / β-Catenin Signaling Pathway

Pathway Description:

The conserved Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-β, and BMP, within different cell types and tissues. The Wnt ligand is a secreted glycoprotein that binds to Frizzled receptors, leading to the formation of a larger cell surface complex with LRP5/6. Frizzleds are ubiquitinated by ZNRF3 and RNF43, whose activity is inhibited by R-spondin binding to LGR5/6. In this manner R-spondins increase sensitivity of cells to the Wnt ligand. Activation of the Wnt receptor complex triggers displacement of the multifunctional kinase GSK-3β from a regulatory APC/Axin/GSK-3β-complex. In the absence of Wnt-signal (Off-state), β-catenin, an integral E-cadherin cell-cell adhesion adaptor protein and transcriptional co-regulator, is targeted by coordinated phosphorylation by CK1 and the APC/Axin/GSK-3β-complex leading to its ubiquitination and proteasomal degradation through the β-TrCP/Skp pathway. In the presence of Wnt ligand (On-state), the co-receptor LRP5/6 is brought in complex with Wnt-bound Frizzled. This leads to activation of Dishevelled (Dvl) by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK-3β from APC/Axin through an unclear mechanism that may involve substrate trapping and/ or endosome sequestration. Stablized β-catenin is translocated to the nucleus via Rac1 and other factors, where it binds to LEF/TCF transcription factors, displacing co-repressors and recruiting additional co-activators to Wnt target genes. Additionally, β-catenin cooperates with several other transcription factors to regulate specific targets. Importantly, researchers have found β-catenin point mutations in human tumors that prevent GSK-3β phosphorylation and thus lead to its aberrant accumulation. E-cadherin, APC, R-spondin and Axin mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. Wnt signaling has also been shown to promote nuclear accumulation of other transcriptional regulator implicated in cancer, such as TAZ and Snail1. Furthermore, GSK-3β is involved in glycogen metabolism and other signaling pathways, which has made its inhibition relevant to diabetes and neurodegenerative disorders.

Selected Reviews:

Angers S, Moon RT (2009) Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol. 10(7), 468–77.

Cadigan KM, Waterman ML (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4(11), .

Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149(6), 1192–205.

de Lau W, Peng WC, Gros P, Clevers H (2014) The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 28(4), 305–16.

Fearon ER (2009) PARsing the phrase "all in for Axin"- Wnt pathway targets in cancer. Cancer Cell 16(5), 366–8.

MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17(1), 9–26.

Metcalfe C, Bienz M (2011) Inhibition of GSK3 by Wnt signalling--two contrasting models. J. Cell. Sci. 124(Pt 21), 3537–44.

Niehrs C (2012) The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13(12), 767–79.

Nusse, R (2010) The Wnt Homepage.

Petersen CP, Reddien PW (2009) Wnt signaling and the polarity of the primary body axis. Cell 139(6), 1056–68.

Sokol SY (2011) Maintaining embryonic stem cell pluripotency with Wnt signaling. Development 138(20), 4341–50.

van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136(19), 3205–14.

Valenta T, Hausmann G, Basler K (2012) The many faces and functions of β-catenin. EMBO J. 31(12), 2714–36.

We would like to thank Prof. Kenneth Cadigan, University of Michigan, Ann Arbor, MI, for contributing to this diagram.

created January 2003 revised July 2014

- See more at: http://www.cellsignal.com/common/content/content.jsp?id=pathways-wnt#sthash.GsjTLbj5.dpuf