The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

/pdf/the-basics-of-epithelial-mesenchymal-transition-xe9crzoewf.pdf

The basics of epithelial-mesenchymal transition

Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

The actin cytoskeleton mediates a variety of essential biological functions in all eukaryotic cells. In addition to providing a structural framework around which cell shape and polarity are defined, its dynamic properties provide the driving force for cells to move and to divide. Understanding the biochemical mechanisms that control the organization of actin is thus a major goal of contemporary cell biology, with implications for health and disease. Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and furthermore, through their interaction with multiple target proteins, they ensure coordinated control of other cellular activities such as gene transcription and adhesion.

/pdf/rho-gtpases-and-the-actin-cytoskeleton-zsfyn1yhxi.pdf

Rho GTPases and the Actin Cytoskeleton

https://www.cell.com/cell/pdf/S0092-8674(03)00432-X.pdf

Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

Small molecule inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction pathways whose activities contribute to human diseases. Transforming growth factor beta (TGF-beta) is a member of a large family of pleiotropic cytokines that are involved in many biological processes, including growth control, differentiation, migration, cell survival, adhesion, and specification of developmental fate, in both normal and diseased states. TGF-beta superfamily members signal through a receptor complex comprising a type II and type I receptor, both serine/threonine kinases. Here, we characterize a small molecule inhibitor (SB-431542) that was identified as an inhibitor of activin receptor-like kinase (ALK)5 (the TGF-beta type I receptor). We demonstrate that it inhibits ALK5 and also the activin type I receptor ALK4 and the nodal type I receptor ALK7, which are very highly related to ALK5 in their kinase domains. It has no effect on the other, more divergent ALK family members that recognize bone morphogenetic proteins (BMPs). Consistent with this, we demonstrate that SB-431542 is a selective inhibitor of endogenous activin and TGF-beta signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways or on components of the signaling pathways activated in response to serum.

SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7.

The Rho family GTPases RhoA, Racl , and CDC42Hsregulate transcriptional activation by SRF

Transcriptional Regulation by Extracellular Signals: Mechanisms and Specificity

Ligands of the transforming growth factor-beta (TGFbeta) superfamily of growth factors initiate signal transduction through a bewildering complexity of ligand-receptor interactions. Signalling then converges to nuclear accumulation of transcriptionally active SMAD complexes and gives rise to a plethora of specific functional responses in both embryos and adult organisms. Current research is focused on the mechanisms that regulate SMAD activity to evoke cell-type-specific and context-dependent transcriptional programmes. An equally important challenge is understanding the functional role of signal strength and duration. How are these quantitative aspects of the extracellular signal regulated? How are they then sensed and interpreted, and how do they affect responses?

TGFβ–SMAD signal transduction: molecular specificity and functional flexibility

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(04)00077-5.pdf

Caroline S. Hill

Papers

SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7.

The Rho family GTPases RhoA, Racl , and CDC42Hsregulate transcriptional activation by SRF

Transcriptional Regulation by Extracellular Signals: Mechanisms and Specificity

TGFβ–SMAD signal transduction: molecular specificity and functional flexibility

New insights into TGF-beta-Smad signalling.