TGF-β Family Signaling in the Control of Cell Proliferation and Survival

Abstract

The transforming growth factor β (TGF-β) family controls many fundamental aspects of cellular behavior. With advances in the molecular details of the TGF-β signaling cascade and its cross talk with other signaling pathways, we now have a more coherent understanding of the cytostatic program induced by TGF-β. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated by TGF-β and determine a cell's proliferation and survival, apoptosis, dormancy, autophagy, and senescence. The difficulty in defining TGF-β's roles partly stems from the context-dependent nature of TGF-β signaling. Here, we review our current understanding and recent progress on the biological effects of TGF-β at the cellular level, with the hope of providing a framework for understanding how cells respond to TGF-β signals in specific contexts, and why disruption of such mechanisms may result in different human diseases including cancer.

Figure 1.

The transforming growth factor β (TGF-β) signaling pathway and its context-dependent regulation. (Left) A schematic diagram of TGF-β signaling. (Right) TGF-β signaling is regulated at several levels by context-dependent factors: (1) Different combinations of paired type I and type II receptors allow for diverse ligand binding as well as intracellular signaling. (2) Accessory proteins at the plasma membrane that regulate the binding efficiency and specificity of TGF-β to their receptors influence downstream responses. (3) Proteins that regulate the recruitment and access of R-Smads to TGF-β receptors. (4) Several proteins regulate TGF-β signaling by posttranslational modification of R-Smads or by preventing their association with TGF-β receptors. (5) A specific TGF-β response can be determined by the expression and activity of transcription cofactors.

Figure 2.

The transforming growth factor β (TGF-β)-mediated cytostatic program in epithelial cells. (A) TGF-β suppresses the expression of transcription factors that regulate growth control including those encoding c-Myc and Id family members. (B) TGF-β induces the expression of several cyclin-dependent kinase (CDK) inhibitors, including p15^INK4B and p21^CIP1. TGF-β also increases p27^KIP1 activity without changing the transcription of CDKN1B gene, partly because increased p15^INK4B disrupts existing p27^KIP1-CDK4/6-cyclin D complexes. (C) TGF-β also suppresses cell-cycle progression by repressing the expression and activity of Cdc25A and inducing expression of 4EBP1.

Figure 3.

A schematic diagram illustrating possible mechanisms of transforming growth factor β (TGF-β)-induced apoptosis. The displayed mechanisms are described in distinct cell types. The balance between TGF-β and phosphoinositide 3-kinase (PI3K)-Akt signaling is essential for determining whether a cell will undergo apoptosis in response to TGF-β.

Figure 4.

Regulation of cellular senescence by transforming growth factor β (TGF-β) signaling. TGF-β family proteins are able to promote cellular senescence in normal and tumor cells through multiple molecular mechanisms, including transcriptional induction of the expression of cell-cycle inhibitors, repression of telomerase expression, and convergent regulation with the p53 pathway.