The International Journal of Biochemistry & Cell Biology
Signalling networks in focusA portrait of Transforming Growth Factor β superfamily signalling: Background matters
Introduction
The TGF-β superfamily of secreted growth factors comprises 33 ligands that, despite exhibiting pronounced structural similarities, function as regulators of a variety of divergent processes both during embryogenesis and later on in adult homeostasis. In addition to the prototypic members, TGF-βs 1,2,3, the family features 10 Bone Morphogenetic Proteins (BMPs), 11 Growth and Differentiation Factors (GDFs), 5 activins/inhibins, nodal, two leftys, and Anti-Muellerian Hormone (AMH) (Derynck and Miyazono, 2007). TGF-β superfamily pathways have evolved from primitive species to vertebrates (Moustakas and Heldin, 2009). The general mechanisms and functions of their signalling pathways have been elucidated since the first discovery of TGF-β, however, intensive research during the past decades has shed light on additional layers of complexity, both regarding their signalling mechanisms and their functions.
In consequence of a prominent role of TGF-β superfamily signalling in disease-related conditions, its pathologic aspects came into light, and its pathways are intensively studied with regard to therapeutic intervention (Gordon and Blobe, 2008).
In this brief review we will (i) describe the pleiotropic functions of TGF-β superfamily pathways with a focus on the molecular mechanisms of signal transduction by these growth factors, (ii) depict the consequences of aberrant signal activity, and (iii) finally summarize therapeutic approaches to target or employ the pathways.
Section snippets
Functions of TGF-βs and BMPs
The best established role of TGF-β in the adult organism is its function as a tumour suppressor (Massagué, 2008). In normal epithelia and in early tumourigenic cells TGF-β signalling prevents uncontrolled growth by inducing cell cycle arrest and apoptosis (Fig. 1) through repression of cyclin dependent kinases (CDKs) and mitogenic c-MYC. Concomitantly, TGF-β upregulates CDK inhibitors p15INK4B and p21Cip1, leading to G1 phase arrest. Induction of apoptosis by TGF-β requires death-associated
Activation of TGF-β signalling cascades by their receptors
All TGF-βs and most BMPs are secreted as pro-peptides in which the mature growth factor domain is non-covalently attached to a pro-domain. In this complex, some ligands are inactive and require activation in the extracellular matrix (TGF-β1, -2, -3; BMP-10, GDF-8), while activation is not required for others (BMP-4, -5, -7) (Sengle et al., 2011). Both TGF-β and BMPs bind to their cell surface receptors to form heteromeric complexes comprising dimers of type I and type II receptors that interact
Associated pathologies and therapeutic implications
Dysregulation of TGF-β/BMP superfamily signalling was identified as the basis for cancer, cardiovascular, fibrotic, and skeletal diseases. In addition, developmental processes are recapitulated during tissue homeostasis regulation and become aberrant during disease development.
Sporadic mutations in components of TGF-β signalling pathways were found in cancer (e.g. colorectal, pancreatic, breast, lung) (Gordon and Blobe, 2008). Hereditary mutations of ALK3, Endoglin, and SMAD4, were identified
Acknowledgements
We thank members of the Knaus Lab for valuable comments on the manuscript.
A.D. was supported by a Berlin Brandenburg School for Regenerative Therapies (BSRT) fellowship.
We wish to apologize to authors whose work could not be cited due to space limitations.
References (39)
- et al.
A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned
Spine J
(2011) - et al.
Emerging role of bone morphogenetic proteins in angiogenesis
Cytokine Growth Factor Rev
(2009) - et al.
Homomeric and heteromeric complexes among TGF-beta and BMP receptors and their roles in signaling
Cell Signal
(2011) - et al.
Role of transforming growth factor-beta superfamily signaling pathways in human disease
Biochim Biophys Acta
(2008) - et al.
Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding
Mol Cell
(2008) - et al.
The TGFbeta receptor activation process: an inhibitor- to substrate-binding switch
Mol Cell
(2001) TGFbeta in cancer
Cell
(2008)- et al.
Intricacies of BMP receptor assembly
Cytokine Growth Factor Rev
(2009) - et al.
The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways
J Biol Chem
(2002) BMPs: from bone morphogenetic proteins to body morphogenetic proteins
Cytokine Growth Factor Rev
(2005)
How the Smads regulate transcription
Int J Biochem Cell Biol
Prodomains of transforming growth factor beta (TGFbeta) superfamily members specify different functions: extracellular matrix interactions and growth factor bioavailability
J Biol Chem
Mechanisms of TGF-beta signaling from cell membrane to the nucleus
Cell
Transforming growth factor beta can stimulate Smad1 phosphorylation independently of bone morphogenic protein receptors
J Biol Chem
TGF-beta superfamily signaling in embryonic development and homeostasis
Dev Cell
Structure of the ternary signaling complex of a TGF-beta superfamily member
Proc Natl Acad Sci USA
Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression
Proc Natl Acad Sci USA
Transforming growth factor beta-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth
Mol Cell Biol
Dorsal–ventral patterning and neural induction in Xenopus embryos
Annu Rev Cell Dev Biol
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