Recent advances in understanding contextual TGFβ signaling

Abstract

The appearance of the first animal species on earth coincides with the emergence of transforming growth factor β (TGFβ) pathways. The evolution of these animals into more complex organisms coincides with a progressively increased TGFβ repertoire through gene duplications and divergence, making secreted TGFβ molecules the largest family of morphogenetic proteins in humans. It is therefore not surprising that TGFβ pathways govern numerous aspects of human biology from early embryonic development to regeneration, hematopoiesis, neurogenesis, and immunity. Such heavy reliance on these pathways is reflected in the susceptibility to minor perturbations in pathway components that can lead to dysregulated signaling and a diverse range of human pathologies such as cancer, fibrosis, and developmental disorders. Attempts to comprehensively resolve these signaling cascades are complicated by the long-recognized paradoxical role the pathway plays in cell biology. Recently, several groups have probed examples of the disparate aspects of TGFβ biology in a variety of animal models and uncovered novel context-dependent regulatory mechanisms. Here, we briefly review recent advancements and discuss their overall impact in directing future TGFβ research.

Keywords: TGFβ signalling; cancer; cancer-associated stroma; glioma; hematopoiesis; hippo pathway; immunity.; stem cells.

Figure 1.. Context-dependent transforming growth factor β TGFβ superfamily signaling.

Diverse biological activities regulated by TGFβ pathways are rigorously controlled in a finely calibrated contextual framework. Perturbation in these processes can lead to disease development.

Figure 2.. Transforming growth factor β TGFβ signaling during homeostasis and cancer.

In mammals, TGFβ1 activates TGFβ receptors to recruit the canonical Smad2/3–Smad4 complex that, upon nuclear translocation, promotes quiescence and induces lethal epithelial-mesenchymal transition (EMT) to limit tumor growth. Loss of Smad4 in Kras ^G12D-mutant cells as well as acquisition of a BRAF ^V600E mutation divert the activity of phosphorylated Smad2/3 to promote cell proliferation, survival, and metastatic growth. Similarly, Drosophila Decapentaplegic (Dpp) stimulates Punt (Put) and Thickveins (Tkv) receptors to activate the canonical Mad-Med (Smad4 homologue) nuclear complex that promotes quiescence. Overactivation of epidermal growth factor receptor (EGFR)/Fos and Jak/signal transducer and activator of transcription (STAT) signaling re-directs Dpp to activate the alternate Put–Saxophone (Sax) receptor complex. This complex then activates dSmad2, which translocates into the nucleus independently of Med and induces tumor-like stem cell growth and dysplasia.