The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

Abstract

The Transforming Growth Factor beta (TGFβ) and Bone Morphogenic Protein (BMP) pathways intersect at multiple signaling hubs and cooperatively or counteractively participate to bring about cellular processes which are critical not only for tissue morphogenesis and organogenesis during development, but also for adult tissue homeostasis. The proper functioning of the TGFβ/BMP pathway depends on its communication with other signaling pathways and any deregulation leads to developmental defects or diseases, including fibrosis and cancer. In this review we explore the cellular and physio-pathological contexts in which the synergism or antagonism between the TGFβ and BMP pathways are crucial determinants for the normal developmental processes, as well as the progression of fibrosis and malignancies.

Keywords: BMPs; Non-SMAD signaling; SMAD pathway; TGFβ; adult homeostasis; cancer; development; disease; fibrosis; signaling.

Figure 1

Essential overview of TGFβ and BMP signaling pathways. For simplicity, many details are omitted, and indirect connections are represented as single arrows. Transcription factors or DNA interacting proteins/kinases/other types of intracellular mediators, are represented as blue/orange/maroon boxes, respectively. SRF = Serum Response Factor; TCF = T Cell Factor; LEF = Lymphoid enhancer-binding factor; AP-1 = Activator Protein-1; ATF2 = Activating Transcription Factor 2; CREB = cAMP response element Binding Protein; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; ERK = Extracellular Signal Regulated Kinase; JNK = c-Jun N-terminal kinase; TAB1/2 = TGF-beta-activated kinase 1 and MAP3K7-binding protein 1/2; TAK1 = Mitogen-activated protein kinase kinase kinase 7.

Figure 2

TGFβ and BMP interplay in bone and heart formation. (a) TGFβ can drive the differentiation of MSCs into chondrocytes or osteoblasts depending on the functional coupling with other factors, such as activin and Wnt, respectively. BMPs can induce the differentiation of these cells, but also block the production by osteoclasts of coupling factors that stimulate bone matrix synthesis activity by osteoblasts. TGFβR2 signaling is necessary to attenuate the PTH signaling that, in turn, enhances the production of BMP2, which can regulate the trabecular/cortical bone ratio. (b) AV myocardial cells require BMP2, TGFβ2, and activated Notch signaling status in endocardial endothelial cells to achieve multiple phases of heart development. BMP2 produced by myocardial cells induces the expression of Notch1 and TGFβ2 in endocardial endothelial cells. Notch1 and TGFβ2 signaling activate the EMT program that is required by these cells to invade the cardiac jelly in the early step of heart valve formation.

Figure 3

TGFβ and BMP interplay in kidney, lungs, liver and heart fibrosis. (a) In tubular epithelial cells TGFβ and BMP7 reciprocally oppose each other’s effects on fibrosis through regulating the expression of key miRNAs with antagonist functions. In mesangial cells BMP7 counteracts TGFβ pro-fibrotic activity via a SMAD5/6 mechanism that prevents SMAD3 nuclear accumulation, and subsequent MMP2 inhibition. (b) BMP2 can prevent the TGFβ-induced trans-differentiation of HSCs in MFBs through downregulating the expression of TGFβ itself and its receptors. By a more indirect mechanism (as in heart fibrosis), BMP2 can also counteract TGFβ-induced EMT. Arrows are colored according to organs of reference. HSC = hepatic stellate cell; FB = fibroblast; MFB = myofibroblast; EC = epithelial cell. Fibrosis limiting/promoting ligands are enclosed in green/orange boxes, respectively.

Figure 4

TGFβ and BMP interplay in tumor dormancy, growth and invasion. (a) TGFβ and BMPs pathways can cooperate to induce tumor dormancy. However, non-canonical TGFβ-activated PI3K/AKT signaling can promote the exit from dormancy and re-enable tumor cell proliferation. (b) TGFβ and BMPs play prevalently counteractive roles in tumor cell growth and invasion. The TGFβ/SMAD2 axis may induce cell cycle arrest in early phases of tumorigeneses (such as in HCC). However, at later tumor stages SMAD-independent TGFβ signaling is suggested to promote events that result in cell growth enhancement, the EMT, and invasiveness. Overall BMPs act to limit tumor cell proliferation and invasion, and TGFβ tumor-promoting actions may rely on the offsetting of BMPs dependent signals. Tumor limiting/promoting ligands are enclosed in green/orange boxes, respectively.