TGFβ: a sleeping giant awoken by integrins

doi:10.1016/j.tibs.2010.08.002

Trends in Biochemical Sciences

Volume 36, Issue 1, January 2011, Pages 47-54

https://doi.org/10.1016/j.tibs.2010.08.002 Get rights and content

Transforming growth factor beta (TGFβ) controls numerous cellular responses, including proliferation, differentiation, apoptosis and migration. This cytokine is produced by many different cell types and has been implicated in the pathogenesis of many diseases, ranging from autoimmune disorders and infectious diseases to fibrosis and cancer. However, TGFβ is always produced as an inactive complex that must be activated to enable binding to its receptor and subsequent function. Recent evidence highlights a crucial role for members of the integrin receptor family in controlling the activation of TGFβ. These pathways are important in human health and disease, and new insights into the biochemical mechanisms that allow integrins to control TGFβ activation could prove useful in the design of therapeutics.

Section snippets

TGFβ is produced as an inactive complex

Transforming growth factor beta (TGFβ) is a critical multi-functional cytokine and founding member of the TGFβ superfamily of molecules. Three isoforms of TGFβ exist (TGFβ1, -2 and -3), all of which are conserved and show similar functional properties in vitro. However, knockout mice lacking individual TGFβ isoforms show distinct phenotypes, suggesting strongly that each isoform has specific and non-overlapping functions in vivo [1].

TGFβ functions by binding to its receptor and activating

The structure of latent TGFβ

Each TGFβ isoform is encoded by separate genes that each encode a 25 kDa N-terminal propeptide termed latency-associated peptide (LAP) and a 12.5 kDa C-terminal active TGFβ moiety, which form a homodimeric LAP–TGFβ propeptide complex (Figure 1). LAP and TGFβ are cleaved in the Golgi by the protease furin; this event is important for the efficient production and subsequent function of TGFβ in vivo [3]. However, the cleaved LAP–TGFβ remains non-covalently associated upon secretion, which blocks

A critical role for integrins in activating the latent complex of TGFβ

A number of different processes have been proposed to activate latent TGFβ. These include heat, acidic pH, reactive oxygen species, various proteases, the membrane glycoprotein thrombospondin-1 [2] and shear stress [8]. However, recent compelling evidence has suggested that, in many physiological situations, the key activators of TGFβ are integrins.

Integrins are a large family of cell adhesion and signaling receptors, consisting of an α and a β subunit that combine to form a heterodimeric type

Integrins αvβ3 and αvβ5

Integrins αvβ3 and αvβ5 are both expressed in many different cell types; however, in most cells, there is little evidence to support a role for these integrins in TGFβ activation. Indeed, mice lacking either αvβ3, αvβ5 or both do not display any steady-state pathology associated with decreased TGFβ activation 20, 21, 22. However, evidence does suggest that both αvβ3 and αvβ5 can activate TGFβ when expressed in certain fibroblastic cells. Dermal fibroblasts from patients with the autoimmune

How do integrins activate TGFβ?

All TGFβ-binding integrins interact with the RGD integrin-binding motif in the LAP region of the latent complex, but how does this interaction result in the generation of active TGFβ? Evidence suggests that different integrins can activate TGFβ in one of two distinct ways.

Concluding remarks

Although it has been appreciated for decades that the powerful cytokine TGFβ is produced as a latent complex that must be activated to function, only in recent years have important mechanisms of TGFβ activation in vivo been uncovered, with integrins taking center stage. The recent findings that specific integrin receptors play a key role in regulating TGFβ activity in many biological settings, including development, control of immune homeostasis and during pathogenesis of a range of diseases,

Acknowledgements

We thank Prof. Dean Sheppard (University of California, San Francisico) and Prof. Charles Streuli (University of Manchester) for their helpful comments on the manuscript. Work in the Travis laboratory is supported by the Biotechnology and Biological Sciences Research Council (BBSRC).

References (71)

Y. Shi et al.
Mechanisms of TGF-β signaling from cell membrane to the nucleus
Cell
(2003)
K.L. Walton
Two distinct regions of Latency-associated Peptide coordinate stability of the Latent Transforming Growth Factor-β1 complex
J. Biol. Chem.
(2010)
K. Janssens
Transforming growth factor-β1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein
J. Biol. Chem.
(2003)
T. Saito
Domain-specific mutations of a transforming growth factor (TGF)-β1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-β1
J. Biol. Chem.
(2001)
J. Ahamed
In vitro and in vivo evidence for shear-induced activation of latent transforming growth factor- β1
Blood
(2008)
R.O. Hynes
Integrins: bidirectional, allosteric signaling machines
Cell
(2002)
J.S. Munger
The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis
Cell
(1999)
B.L. Bader
Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all αv integrins
Cell
(1998)
Y. Asano
Involvement of αvβ5 integrin in the establishment of autocrine TGF-β signaling in dermal fibroblasts derived from localized scleroderma
J. Invest. Dermatol.
(2006)
Y. Asano
Increased expression of integrin αvβ5 induces the myofibroblastic differentiation of dermal fibroblasts
Am. J. Pathol.
(2006)

T. Tabata

Induction of an epithelial integrin αvβ6 in human Cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-β1 and increased collagen production

Am. J. Path.

(2008)

F. Ghannad

Absence of αvβ6 integrin is linked to initiation and progression of periodontal disease

Am. J. Pathol.

(2008)

K. Hahm

αvβ6 integrin regulates renal fibrosis and inflammation in Alport mouse

Am. J. Pathol.

(2007)

L.-J. Ma

Transforming growth factor-β-dependent and -independent pathways of induction of tubulointerstitial fibrosis in β6^–/– mice

Am. J. Pathol.

(2003)

E. Patsenker

Inhibition of integrin αvβ6 on cholangiocytes blocks transforming growth factor-β activation and retards biliary fibrosis progression

Gastroenterology

(2008)

M.R. Morgan

The integrin cytoplasmic-tail motif EKQKVDLSTDC Is sufficient to promote tumor cell invasion mediated by matrix metalloproteinase (MMP)-2 or MMP-9

J. Biol. Chem.

(2004)

S. Cambier

Integrin αvβ8-Mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch

Am. J. Pathol.

(2005)

H. Su

Reduced expression of integrin αvβ8 is associated with brain arteriovenous malformation pathogenesis

Am. J. Pathol.

(2010)

Z.Y. Mu

TGFβ1 and TGFβ3 are partially redundant effectors in brain vascular morphogenesis

Mech. Dev.

(2008)

L. Gorelik et al.

Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease

Immunity

(2000)

M.O. Li

Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms

Immunity

(2006)

J.C. Marie

Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor

Immunity

(2006)

M.Y. Xu

Lysophosphatidic acid induces αvβ6 integrin-mediated TGF-β activation via the LPA2 receptor and the small G protein Gαq

Am. J. Pathol.

(2009)

J.A. Markovics

Transcription of the transforming growth factorβ (TGF-β) activating integrin β8 subunit is regulated by SP3, AP-1 and the p38 pathway

J. Biol. Chem.

(2010)

A. Cuenda et al.

p38 MAP-Kinases pathway regulation, function and role in human diseases

Biochim. Biophys. Acta

(2007)

J.S. Kang

New regulatory mechanisms of TGF-β receptor function

Trends Cell Biol.

(2009)

J. Groppe

Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding

Mol. Cell

(2008)

W. He

Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway

Cell

(2006)

J.P. Annes

Making sense of latent TGFβ activation

J. Cell Sci.

(2003)

M. Pesu

T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance

Nature

(2008)

Y. Tang

TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation

Nat. Med.

(2009)

M.J. Humphries

Integrin structure

Biochem. Soc. Trans.

(2000)

Y. Asano

Increased expression of integrin αvβ3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts

J. Immunol.

(2005)

Y. Asano

Involvement of αvβ5 integrin-mediated activation of latent transforming growth factor β1 in autocrine transforming growth factor β signaling in systemic sclerosis fibroblasts

Arthritis Rheum.

(2005)

D. Mu

The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1

J. Cell Biol.

(2002)

Cited by (180)

An engineered (CAGA)<inf>12</inf>-EGFP cell-based biosensor for high-content and accurate detection of active TGF-β
2023, Biosensors and Bioelectronics
Transforming growth factor-β (TGF-β) regulates multiple fundamental physiological processes and is closely related to severe diseases such as cancer, fibrosis, immune disorders and cardiovascular diseases. TGF-β is thus an important biomarker for clinical diagnosis and prognosis, and a crucial target for therapeutics development. Here we describe a high-content, serum-free, easy-to-use, and cost-effective (CAGA)₁₂-EGFP cell-based biosensor for accurate measurements of active TGF-β. Together with non-destructive and continuous measurement protocol and data processing method established here, the biosensor is capable of detecting active TGF-β1 in the range of 0.024–6.25 ng/mL concentration with >91% accuracy and high repeatability. Overall, the engineered (CAGA)₁₂-EGFP biosensor is a powerful tool for detection of active TGF-β and for mechanistic study of the TGF-β pathway. The greatly reduced cost and operating simplicity also makes it a highly potent in vitro platform for high-throughput screening of anti-TGF-β therapeutics.
Biomaterial-induced pathway modulation for bone regeneration
2022, Biomaterials
Embryogenic developmental processes involve a tightly controlled regulation between mechanical forces and biochemical cues such as growth factors, matrix proteins, and cytokines. This interplay remains essential in the mature body, with aberrant pathway signaling leading to abnormalities such as atherosclerosis in the cardiovascular system, inflammation in tendon tissue, or osteoporosis in the bone. The aim of bone regenerative strategies is to develop tools and procedures that will harness the body's own self-repair ability in order to successfully regenerate even very large and complex bone defects and restore normal function. To achieve this, understanding pathways that govern processes of progenitor differentiation towards the osteogenic lineages, their phenotypical maintenance, and the construction of functional bone tissue is imperative to subsequently develop regenerative therapies that mimic these processes. While a body of literature exists that describes how biochemical stimuli guide cell behavior in the culture dish, due to the lack of an appropriate mechanical environment, these signals are often insufficient or inappropriate for achieving a desirable response in the body. Moreover, bone regenerative therapies rarely rely on a biochemical stimulus, such as a growth factor alone, and instead often comprise a carrier biomaterial that introduces a very different microenvironment from that of a cell culture dish. Therefore, in this review, we discuss which biomaterials elicit or influence pathways relevant for bone regeneration and describe mechanisms behind these effects, with the aim to inspire the development of novel, more effective bone regenerative therapies.
SMAD proteins: Mediators of diverse outcomes during infection
2022, European Journal of Cell Biology
Citation Excerpt :
TGF-β, the prototypic family member, is synthesised and secreted bound to the latency-associated peptide as a small latent complex which is biologically inactive (Aashaq et al., 2021; Worthington et al., 2011). This pro-TGF-β dimerises then crosslinks with latent TGF-β binding protein to form the large latent complex, which resides in the extracellular matrix (Tzavlaki and Moustakas, 2020; Worthington et al., 2011). TGF-β is liberated from this complex by integrin-dependent and independent mechanisms before it can interact with cell-surface receptors and initiate signal transduction (Robertson and Rifkin, 2016; Tzavlaki and Moustakas, 2020).
Understanding the relationship between host and pathogen is key to combatting disease. SMAD transcription factors, which transmit TGF-β superfamily signalling, mediate an array of outcomes during embryogenesis, inflammation, cancer, and immunity. Surprisingly, these activities can sometimes be directly opposed; for example, SMAD3 has been reported as tumour suppressor by arresting cell cycle progression but conversely promotes cancer metastasis. A growing body of literature has identified SMADs as prominent targets during viral and bacterial infection for modulating host signalling. During infection, the activity of SMAD-containing transcriptional complexes can be finely tuned by pathogens to enhance infectivity and spread. SMAD signalling can be modulated at many levels, such as upstream at the ligand and receptor, or by direct interactions with SMADs. These alterations can increase pathogen dissemination, induce fibrosis, over-activate, or attenuate the host immune response. Here, we summarise the diverse mechanisms by which pathogens have evolved to sway SMAD signalling in their favour. Understanding the intricacies of host–pathogen interactions through this lens may elucidate aspects of SMAD function in cancer development, homoeostasis, and immune signalling previously overlooked. These insights are an opportunity to identify novel TGF-β or BMP-targeted therapeutics for applications to infectious disease contexts.
Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease
2022, JHEP Reports
Transforming growth factor-β (TGF-β) is a potent effector in the liver, which is involved in a plethora of processes initiated upon liver injury. TGF-β affects parenchymal, non-parenchymal, and inflammatory cells in a highly context-dependent manner. Its bioavailability is critical for a fast response to various insults. In the liver – and probably in other organs – this is made possible by the deposition of a large portion of TGF-β in the extracellular matrix as an inactivated precursor form termed latent TGF-β (L-TGF-β). Several matrisomal proteins participate in matrix deposition, latent complex stabilisation, and activation of L-TGF-β. Extracellular matrix protein 1 (ECM1) was recently identified as a critical factor in maintaining the latency of deposited L-TGF-β in the healthy liver. Indeed, its depletion causes spontaneous TGF-β signalling activation with deleterious effects on liver architecture and function. This review article presents the current knowledge on intracellular L-TGF-β complex formation, secretion, matrix deposition, and activation and describes the proteins and processes involved. Further, we emphasise the therapeutic potential of toning down L-TGF-β activation in liver fibrosis and liver cancer.
The local wound environment is a key determinant of the outcome of TGFβ signaling on the fibrotic response of CD44<sup>+</sup> leader cells in an ex vivo post-cataract-surgery model
2021, Experimental Eye Research
The cytokine transforming growth factor beta (TGFβ) has a role in regulating the normal and pathological response to wound healing, yet how it shifts from a pro-repair to a pro-fibrotic function within the wound environment is still unclear. Using a clinically relevant ex vivo post-cataract surgery model that mimics the lens fibrotic disease posterior capsule opacification (PCO), we investigated the influence of two distinct wound environments on shaping the TGFβ-mediated injury response of CD44⁺ vimentin-rich leader cells. The substantial fibrotic response of this cell population occurred within a rigid wound environment under the control of endogenous TGFβ. However, TGFβ was dispensable for the role of leader cells in wound healing on the endogenous basement membrane wound environment, where repair occurs in the absence of a major fibrotic outcome. A difference between leader cell function in these distinct environments was their cell surface expression of the latent TGFβ activator, αvβ3 integrin. This receptor is exclusively found on this CD44⁺ cell population when they localize to the leading edge of the rigid wound environment. Providing exogenous TGFβ to bypass any differences in the ability of the leader cells to sustain activation of TGFβ in different environments revealed their inherent ability to induce pro-fibrotic reactions on the basement membrane wound environment. Furthermore, exposure of the leader cells in the rigid wound environment to TGFβ led to an accelerated fibrotic response including the earlier appearance of pro-collagen + cells, alpha smooth muscle actin (αSMA)+ myofibroblasts, and increased fibrotic matrix production. Collectively, these findings show the influence of the local wound environment on the extent and severity of TGFβ-induced fibrotic responses. These findings have important implications for understanding the development of the lens fibrotic disease PCO in response to cataract surgery wounding.
TNF-α and IL-1β Do Not Induce Langerhans Cell Migration by Inhibiting TGFβ Activation
2021, JID Innovations
In the skin, Langerhans cells (LCs) require autocrine latent TGFβ that is transactivated by the integrins ανβ6 and ανβ8 expressed by keratinocytes (KCs) for long-term epidermal retention. Selective expression of a ligand-independent, constitutively active form of TGFβR1 inhibits LC migration during homeostasis and in response to UVB exposure. In this study, we found that LC migration in response to inflammatory stimuli was also inhibited by ligand-independent TGFβR1 signaling. Contrary to UVB stimulation, which reduced KC expression of ανβ6, in vitro and in vivo exposure to TNF-α or IL-1β increased ανβ6 transcript and protein expression by KCs. This resulted in increased KC-mediated transactivation of latent TGFβ. Expression of ανβ8 was largely unchanged. These findings show that ligand-independent TGFβR1 signaling in LCs can overcome inflammatory migration stimuli, but reduced KC-mediated transactivation of latent TGFβ by KCs may only drive LC migration during homeostasis and in response to UV stimulation.

View all citing articles on Scopus

¹: These authors contributed equally to this work.

View full text

Trends in Biochemical Sciences

ReviewTGFβ: a sleeping giant awoken by integrins

Section snippets

TGFβ is produced as an inactive complex

The structure of latent TGFβ

A critical role for integrins in activating the latent complex of TGFβ

Integrins αvβ3 and αvβ5

How do integrins activate TGFβ?

Concluding remarks

Acknowledgements

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Blood

Cell

Cell

Cell

J. Invest. Dermatol.

Am. J. Pathol.

Am. J. Path.

Am. J. Pathol.

Am. J. Pathol.

Am. J. Pathol.

Gastroenterology

J. Biol. Chem.

Am. J. Pathol.

Am. J. Pathol.

Mech. Dev.

Immunity

Immunity

Immunity

Am. J. Pathol.

J. Biol. Chem.

Biochim. Biophys. Acta

Trends Cell Biol.

Mol. Cell

Cell

Making sense of latent TGFβ activation

J. Cell Sci.

T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance

Nature

TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation

Nat. Med.

Integrin structure

Biochem. Soc. Trans.

Increased expression of integrin αvβ3 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts

J. Immunol.

Involvement of αvβ5 integrin-mediated activation of latent transforming growth factor β1 in autocrine transforming growth factor β signaling in systemic sclerosis fibroblasts

Arthritis Rheum.

The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1

J. Cell Biol.

Review
TGFβ: a sleeping giant awoken by integrins