Signalling networks in focus
A portrait of Transforming Growth Factor β superfamily signalling: Background matters

https://doi.org/10.1016/j.biocel.2011.12.013Get rights and content

Abstract

Ligands of the Transforming Growth Factor β superfamily like Transforming Growth Factor β and Bone Morphogenetic Proteins govern developmental processes and regulate adult homeostasis by controlling cellular proliferation, survival, differentiation and migration. Aberrant signalling activity is associated with human disorders such as cancer, cardiovascular, musculoskeletal, or fibrotic disease. Upon binding to specific sets of cognate cell surface receptors, family members induce highly similar pathways which include canonical SMAD dependent signalling as well as pathways without direct involvement of SMAD proteins, which activate signalling molecules like mitogen-activated protein kinases or small GTPases. The diverse ligand functionalities are achieved through regulation and modulation of the pathways at all levels, resulting in a highly quantitative and context sensitive signal integration reflecting the cellular state and background. Strategies to target Transforming Growth Factor β or Bone Morphogenetic Protein pathways have been developed on the basis of our current understanding and have proven a highly beneficial potential.

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.

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