1. Nat. Rev. Urol. doi:10.1038/nrurol.2018.22
Figure 3 Key signalling nodes mediating cellular plasticity and neuroendocrine differentiation
Figure 3 | Key signalling nodes mediating cellular plasticity and neuroendocrine differentiation. a | The IL-6–signal transducer and activator of transcription 3 (STAT3) pathway and the WNT–β-catenin signalling pathway converge during epithelial–mesenchymal transition (EMT) and in cancer stem-like cells (CSCs) and neuroendocrine cells to support transcriptome dynamics and plasticity. Briefly, engagement of IL-6 with its receptor, IL-6R, facilitates activation of Janus kinases (JAKs), such as JAK1 and JAK2, which phosphorylate STAT3 at Tyr705; this phosphorylation results in the translocation of activated STAT3 dimers to the nucleus. In the nucleus, STAT3 associates with interferon-stimulated response elements (ISREs) and γ-activated sequences (GASs) to drive the transcription of genes associated with EMT, the CSC phenotype, and neuroendocrine differentiation. The activation of STAT3 is further enforced by canonical WNT signalling; Dishevelled (DVL) associates with the Frizzled (FZD) receptor to sequester glycogen synthase kinase-3β (GSK3β), thereby enabling the stabilization of β-catenin (β-cat) and its translocation to the nucleus. In the nucleus, β-catenin associates with members of the T cell factor (TCF)–lymphoid enhancer factor (LEF) transcription factor family to activate WNT-responsive genes, such as STAT3. Moreover, during non-canonical WNT signalling, activated FZD can associate with and activate the tyrosine-protein kinase FYN; activated FYN can recruit STAT3 and phosphorylate it at Tyr705 to facilitate the nuclear translocation of STAT3 and transcriptional activity. b | Three biological cell states — EMT, stem-like, and neuroendocrine — underlie cell plasticity and, in turn, influence neuroendocrine differentiation. Transcriptomic, functional, and genetic studies reveal that these biological states are interconnected via a network of shared transcription factors, epigenetic regulators, and cell surface receptors. P, phosphorylation;.
Davies, A. H. et al. (2018) Cellular plasticity and the neuroendocrine phenotype in prostate cancer
Nat. Rev. Urol. doi: /nrurol