Reactome | Signaling by TGFB family members

Signaling by TGFB family members

Stable Identifier

R-HSA-9006936

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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The human genome encodes 33 TGF-beta family members, including TGF-beta itself, as well as bone morphogenetic protein (BMP), activin, nodal and growth and differentiation factors (GDFs). This superfamily of ligands generally binds as dimers to hetero-tetrameric cell-surface receptor serine/threonine kinases to activate SMAD-dependent and SMAD-independent signaling (reviewed in Morikawa et al, 2016; Budi et al, 2017).
Signaling by the TGF-beta receptor complex is initiated by TGF-beta. TGF-beta (TGFB1), secreted as a homodimer, binds to TGF-beta receptor II (TGFBR2), inducing its dimerization and formation of a stable hetero-tetrameric complex with TGF-beta receptor I homodimer (TGFBR1). TGFBR2-mediated phosphorylation of TGFBR1 triggers internalization of the heterotetrameric TGF beta receptor complex (TGFBR) into clathrin coated endocytic vesicles and recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates SMAD2 and SMAD3, promoting their association with SMAD4 (known as Co-SMAD). In the nucleus, the SMAD2/3:SMAD4 heterotrimer binds target DNA elements and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation. For a review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
Signaling by BMP is triggered by bone morphogenetic proteins (BMPs). BMPs can bind type I receptors in the absence of type II receptors, but the presence of both types dramatically increases binding affinity. The type II receptor kinase transphosphorylates the type I receptor, leading to recruitment and phosphorylation of SMAD1, SMAD5 and SMAD8, which function as R-SMADs in BMP signalling pathways. Phosphorylated SMAD1, SMAD5 and SMAD8 form heterotrimeric complexes with SMAD4, the only Co-SMAD in mammals. The SMAD1/5/8:SMAD4 heterotrimer regulates transcription of genes involved in development of many tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. For review of BMP signaling, please refer to Miyazono et al. 2010.
Signaling by activin is triggered when an activin dimer (activin A, activin AB or activin B) binds the type II receptor (ACVR2A, ACVR2B). This complex then interacts with the type I receptor (ACVR1B, ACVR1C) and phosphorylates it. The phosphorylated type I receptor phosphorylates SMAD2 and SMAD3. Dimers of phosphorylated SMAD2/3 bind SMAD4 and the resulting ternary complex enters the nucleus and activates target genes. For a review of activin signaling, please refer to Chen et al. 2006.

Literature References

PubMed ID	Title	Journal	Year
19648010	New regulatory mechanisms of TGF-beta receptor function Kang, JS, Derynck, R, Liu, C	Trends Cell Biol	2009
19762341	Bone morphogenetic protein receptors and signal transduction Miyazono, K, Kamiya, Y, Morikawa, M	J Biochem	2010
27141051	TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology Miyazono, K, Derynck, R, Morikawa, M	Cold Spring Harb Perspect Biol	2016
28552280	Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility Derynck, R, Duan, D, Budi, EH	Trends Cell Biol.	2017
21550381	Betaglycan: a multifunctional accessory Stenvers, KL, Bilandzic, M	Mol Cell Endocrinol	2011
16636301	Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis Chuang, J, Chang, CD, Chung, J, Wang, Q, Chen, YG, Lin, SL, Ying, SY	Exp. Biol. Med. (Maywood)	2006
30184463	TGF-β receptors: In and beyond TGF-β signaling Li, X, Vander Ark, A, Cao, J	Cell Signal	2018