The role of TGF-β/SMAD4 signaling in cancer

Abstract

Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.

Keywords: SMAD4; TGF-β; mouse model; prognosis; tumorigenesis.

Figure 1

The structure of SMAD4 and its role as the common mediator for signaling of TGF-β superfamily. (A) Diagrammatic representation of the structure of SMAD4. Abbreviations: NLS, nuclear localization signal; NES, nuclear export signal; SAD, SMAD activation domain; SBE, SMAD binding DNA element. (B) Diagram showing SMAD4 as the common mediator for TGF-β and BMP signaling. TF: transcriptional factor.

Figure 2

Schematic diagram of the interaction between TGF-β/SMAD4 signaling pathway and MAPK (mitogen-activated protein kinase), PI3K/AKT (phosphatidylinositol-3 kinase/AKT) and WNT/β-catenin pathways. The canonical TGF-β/SMAD4 signal initiates from the TGF-β ligand activation and its binding to the type II and I receptors (T-βR II and T-βR I), which then phosphorylates SMAD2/3. The phosphorylated SMAD2/3 form a heterodimeric complex with SMAD4 and translocate to the nucleus and bind to SBE directly and regulate target genes transcription with the help of transcriptional factors. These target genes are mainly involved in growth arrest and apoptosis. (A) RAS/RAF/ERK1/2 axis regulates the TGF-β/SMAD4 pathway by (1) phosphorylating SMAD2 and SMAD3 to prevent its translocation into the nucleus; (2) mediating SMAD4 degradation; and (3) promoting AP-1 complex formation at the TGF-β1 promoter, thus boost the TGF-β1 transcription and secretion. As the substrate of JNK, c-Jun can directly bind to the transcriptional corepressor TG-interacting factor (TGIF) to inhibit SMAD2 dependent transcription. P38 can phosphorylate SMAD binding partners, such as activating transcription factor-2 (ATF-2), in nucleus and therefore facilitates TGF-β/SMAD4 induced genes transcription. (B) PI3K/AKT pathway suppresses the T-βR I mediated SMAD3 phosphorylation through its downstream molecule mTOR. AKT can directly phosphorylate FOXO and keep it in the cytoplasm to prevent its binding to the promoter of p27 and p21, thus blocks the TGF-β/SMAD4 mediated cytostatic signals. (C) β-catenin destruction complex consisting of AXIN, APC, GSK3β and CKIα causes SMAD7 ubiquitination and degradation. And in turn, SMAD7 can disassemble the complex by binding to AXIN, hence stablize β-catenin and promote its nucleus translocation.

Figure 3

Schematic diagram of mutational pattern in exons of SMAD4. Note: SMAD4 gene contains 12 exons, 11 of which were identified at first, and another exon was discovered later at the upstream of exon 1, so it was called exon 0. The exon 11 is about fifty times longer than exon 10, so it is labeled with dash line.