Transforming Growth Factor Beta: Role in Cell Growth and Differentiation

Abstract

Transforming growth factor beta (TGFβ) is the prototype for a family of multifunctional secreted peptides that control many aspects of growth and development in a cell‐type‐specific manner. TGFβs are well conserved among species indicating their importance in these basic biological processes. TGFβ is secreted in a latent form that is activated outside of the cell. It acts by binding to heteromeric serine/threonine kinase receptors on the cell surface that transmit a signal to nucleus via Smad proteins to ultimately regulate changes in gene expression. Although TGFβ is required for normal development and physiology, alterations in TGFβ signalling are involved in many disease processes including cancer, fibrosis and disorders of the connective tissue like Marfan's syndrome. Understanding the basic mechanisms through which TGFβ mediates cell growth, shape, migration and differentiation should lead to therapeutic interventions for a number of common diseases.

Key Concepts:

  • Transforming growth factor beta (TGFβ) is the prototype for a conserved family of multifunctional secreted peptides.

  • TGFβs regulate many basic biological processes including cell proliferation, shape, adhesion, migration and differentiation.

  • TGFβ is secreted from cells in a latent, inactive form that is activated through proteolytic and nonproteolytic mechanisms.

  • TGFβ acts through heteromeric serine/threonine kinase receptors.

  • TGFβ regulates changes in gene expression via Smad proteins.

  • Smad‐independent, noncanonical signalling pathways exist.

  • TGFβ inhibits the cell cycle by regulating the activity of cyclin dependent kinases.

  • TGFβ regulates the expression of key transcription factors, Snail and Slug, which mediate changes in cell shape.

  • TGFβ promotes deposition and accumulation of ECM.

  • TGFβ regulates differentiation through Smads by mediating changes in chromatin structure and binding to master transcriptional regulators.

Keywords: Smad; cancer; cell cycle; extracellular matrix; differentiation

Figure 1.

The TGFβ superfamily. Representative members identified in mouse and humans are shown, except for Drosophila Dpp (decapentaplegic) in brackets. Lines represent the percentage amino acid identity of each member when compared with BMP‐2. BMP, bone morphogenetic protein; GDF, growth and differentiation factor; CDMP, cartilage derived matrix protein and OP, osteogenic protein.

Figure 2.

TGFβ structure. TGFβ is synthesized as a large precursor protein with a signal sequence, prodomain and mature peptide. Two TGFβ molecules are held together to form a dimer by intermolecular disulfide bonds from the conserved cysteine residues. When TGFβ is secreted, the signal sequence is removed by proteolytic cleavage. The prodomain, also referred to as the LAP, remains associated with the dimer resulting in a latent protein complex. Bioactive TGFβ is released when the prodomain is released.

Figure 3.

Model for TGFβ receptor signalling. (1) TGFβ ligand first binds to the type II receptor, a constitutively active serine/threonine kinase. The type II receptor is then able to form a heteromeric complex with the type I receptor. (2) The type II receptor phosphorylates the GS domain of the type I receptor, activating the serine/threonine kinase activity of the type I receptor. The type I receptor then phosphorylates downstream signalling molecules. (3) Smad1, ‐2, ‐3, ‐5 and ‐8 are directly phosphorylated by the type I receptor. Smad2 and ‐3 mediate signalling for TGFβ and activin. Smad1, ‐5 and ‐8 mediate BMP signalling and are therefore not shown here. (4) Phosphorylated Smads form a heteromeric complex with Smad4 and are translocated to the nucleus. (5) Smads act as transcription factors and can either bind to DNA directly or bind in combination with a large array of diverse transcriptional regulators. TGFβ has also been shown to regulate expression of a large number of diverse genes. Changes in gene expression mediate the biological effects of TGFβ. (6) Inhibitory Smads have also been identified. Smad7 competes with other Smads for binding to the type I receptor, preventing phosphorylation and blocking signal propagation. (7) Smurf ubiquitin ligases target Smad for degradation, thereby antagonizing the signal.

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Further Reading

Caja L, Kahata K and Moustakas A (2012) Context dependent action of TGFβ family members on normal and cancer stem cells. Current Pharmaceutical Design 18: 4072–4086.

Kubiczkova L, Sedlarikova L, Hajek R et al. (2012) TGFβ‐ an excellent servant but a bad master. Journal of Translational Medicine 10: 183–207.

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Sigal LH (2012) Basic science for the clinician 57: transforming growth factor β. Journal of Clinical Rheumatology 18(5): 268–272.

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Serra, Rosa(Mar 2014) Transforming Growth Factor Beta: Role in Cell Growth and Differentiation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000934.pub3]