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Review
.2018 Dec 1;444 Suppl 1(Suppl 1):S79-S97.
doi: 10.1016/j.ydbio.2018.02.003. Epub 2018 Feb 14.

MAPK and PI3K signaling: At the crossroads of neural crest development

Affiliations
Review

MAPK and PI3K signaling: At the crossroads of neural crest development

Colin J Dinsmore et al. Dev Biol..

Abstract

Receptor tyrosine kinase-mediated growth factor signaling is essential for proper formation and development of the neural crest. The many ligands and receptors implicated in these processes signal through relatively few downstream pathways, frequently converging on the MAPK and PI3K pathways. Despite decades of study, there is still considerable uncertainty about where and when these signaling pathways are required and how they elicit particular responses. This review summarizes our current understanding of growth factor-induced MAPK and PI3K signaling in the neural crest.

Keywords: AKT; Cell signaling; ERK; Receptor Tyrosine kinases.

Copyright © 2018 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1. RTK signaling pathways in isolation
The ERK1/2 (A), p38 (B), JNK (C) ERK5 (D), and PI3K (E) pathways and their known or likely means of activation downstream of RTKs are shown at left. For simplicity only crucial adapter proteins are shown and specific effector proteins and crosstalk between pathways have been omitted. See the text for further clarification. To the right are demonstrated (bold) and suggested (regular) cellular downstream behaviors in NC.
Figure 2
Figure 2. RTK signaling pathways acting in concert
A generic RTK is shown at center in an activated state. Signaling proteins that activate the MAPK pathways (e.g. GRB2-SOS) and PI3K pathway (e.g. p85α) can be recruited directly to the RTK or via signaling effectors that act as intermediates (e.g. FRS2/3, SHB/SHC, CRK/CRKL, SHP2, GRB7/10/14, IRS1/2, etc.). Many of these proteins can recruit one another and receptor activation thereby creates multimeric signaling complexes. The exact composition of effectors and activated pathways will depend on the RTK, ligand, and cell type involved. MAPK signaling regulates cytoplasmic targets such as MAPKAPs, cytoskeletal proteins, and apoptosis/survival proteins, and nuclear targets, mainly transcription factors. Some MAPKAPS will translocate to the nucleus and regulate TFs, potentiating the response. PI3K activity can activate Rho-family GTPases that regulate the cytoskeleton and cytoskeleton-regulated TFs (e.g. MKL1/2), and activate AKT signaling, which in turn regulates p53, FOXO, and mTORC1 activity. MAPK and PI3K can regulate each other and some of this crosstalk is shown (e.g. AKT inhibition of RAF). MAPK and PI3K can also be activated by other receptors or cellular stress and these sources are shown in a lighter tone. Last, RTKs can activate additional signaling pathways not covered in this review (PLCγ, PKC, Src Family Kinases, and STATs). While many of these pathways can interact with MAPK and PI3K pathways, they are omitted for clarity. Effectors and pathways more associated with MAPK signaling are shown in blue tones and green tones, while those more tightly associated with PI3K signaling are shown in red and orange themes, though the high degree of interconnectedness makes such distinctions somewhat contrived.
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