Mitogen-activated protein kinases and Wnt/β-catenin signaling

Abstract

Wnt/β-catenin canonical pathway is critical for normal embryonic development; mutations and aberrant expression of specific components of this pathway can be oncogenic. Mitogen-activated protein kinase (MAPK) pathways, prominent in intracellular signaling, have been shown to have unique and provocative roles that impact the Wnt/β-catenin signaling. We discuss recent insights that implicate the three major pathways of the MAPK network, i.e., mediated by p38, c-Jun N-terminal (JNK) kinase, and Extra-cellular-Regulated Kinases (ERK) and their downstream signaling elements in Wnt/β-catenin signaling. Novel “crosstalk” among MAPK and Wnt/β-catenin canonical signalling pathways is essential. A fuller understanding of how such signaling is integrated during development is a high-value target for future research.

Acknowledgements

We thank Dr. H.-Y. Wang, Department of Physiology and Biophysics, State University of New York at Stony Brook, for the critical reading of the manuscript. We also thank members of the Malbon and Wang laboratories for their constant support and encouragement. This work has been generously supported by USPHS research awards from the National Institutes of Diabetes, Digestive, and Kidney Disease, National Institutes of Health to Craig C. Malbon.

Figures and Tables

Figure 1 Mitogen-activated protein kinase pathways. Mitogen-activated protein kinase (MAPK) pathways are stimulated by a variety of extra-cellular stimuli, including, growth factors, cytokines or environmental stress. The MAPK cascades constitute three sequentially activated kinase complexes. MAPKs, which include p38, c-Jun N-terminal kinase (JNK) and Extra-cellular regulated kinase (ERK) are substrates for phosphorylation by MAP kinase kinases (MKKs). The MAP kinase kinases are in turn phosphorylated by MAP kinase kinase kinases (MEKKs). The activated MAPK ultimately induce an appropriate cellular response. Different stimuli activate either p38 or JNK or ERK pathways via different combinations of MEKKs and MKKs. Note: for more information on MAP kinase proteins and their upstream kinases refer to Dong et al.2

Figure 2 Wnt/-catenin signaling pathway. Wnts are secreted glycoproteins that bind to their cognate receptors, Frizzleds. Frizzleds belong to a family of heptahelical, G-protein-coupled receptors that bind specific Wnts and transduce the signal to downstream signalling pathways. Under basal conditions, cellular -catenin is phosphorylated by a Serine/Threonine kinase, Glycogen Synthase Kinase-3 (GSK3) in a complex along with Axin, adenomatous polyposis coli (APC) and other elements. The phosphorylated -catenin is constantly subjected to a proteasome-mediated degradation. Wnt-activated Frizzled (with its co-receptor low-density lipoprotein-related receptor protein-6 (LRP6)) activate the downstream signalling components including G-proteins, G_o and G_q, and a phosphoprotein, Dishevelled. Dishevelleds, by an unclear mechanism, lead to reduced GSK3 kinase activity. Suppression of GSK3 activity leads to elevation of cytosolic and nuclear -catenin levels. Elevated nuclear -catenin levels activates the lymphoid-enhancer factor/T-cell factor (Lef/Tcf)-sensitive transcription, turning on the genes that are necessary for development. Note: for complete list of proteins involved in Wnt signalling, refer to the Wnt home page (http://www.stanford.edu/~rnusse/wntwindow.html).

Figure 3 Conversations between Wnt/β-catenin and MAPK signaling pathways. Wnt ligands apart from activating Wnt/β-catenin pathway also activate MAPK pathways. Wnts induce a strong activation of p38 MAPK and this activation is G-protein and Dishevelled dependent. Wnt-activated p38 MAPK regulates Wnt/β-catenin signalling by inactivating GSK3β kinase activity. Similarly, Wnt-induced JNK activation occurs through G-proteins, Dishevelleds, small molecular weight GTPases (RhoA, Rac1, Cdc42), MEKKs and MKKs. Activated JNK phosphorylates its prime substrate, c-Jun, that ultimately leads induction of planar cell polarity. The phosphorylated c-Jun may also translocate into the nucleus and along with nuclear Dishevelled regulates Lef/Tcf-sensitive gene transcription. ERKs are also activated by Wnt through Raf1/MEK/pERK pathway and induce cell proliferation. In addition, the activated ERKs may also translocate into the nucleus and regulate the Lef/Tcf-sensitive gene transcription.