Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis

Abstract

Transforming growth factor-b (TGF-b) superfamily members signal via membrane-bound heteromeric serinethreonine kinase receptor complexes. Upon ligand-binding, receptor activation leads to phosphorylation of cytoplasmic protein substrates of the Smad family. Following phosphorylation and oligomerization, the latter move into the nucleus to act as transcription factors to regulate target gene expression. TGF-b responses are not solely the result of the activation Smad cascade, but are highly cell-type specific and dependent upon interactions of Smad signaling with a variety of other intracellular signaling mechanisms, initiated or not by TGF-b itself, that may either potentiate, synergize, or antagonize, the rather linear TGF-b/Smad pathway. These include, (a), regulation of Smad activity by mitogen-activated protein kinases (MAPKs), (b), nuclear interaction of activated Smads with transcriptional cofactors, whether coactivators or corepressors, that may be themselves be regulated by diverse signaling mechanisms, and (c), negative feedback loops exerted by inhibitory Smads, transcriptional targets of the Smad cascade. This review focuses on how MAPKs modulate the outcome of Smad activation by TGF-b, and how cross-signaling mechanisms between the Smad and MAPK pathways may take place and affect cell fate in the context of carcinogenesis.

The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor β–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer

“…TGFh signaling and transcription is tightly controlled by a complex network of cellular mechanisms including crosstalk with oncogenic signaling cascades and tumor suppressor pathways (1,11,28). In the context of TGFh signaling in pancreatic cancer cells, the oncogenic Ras-Mek-ERK signaling cascade deserves particular attention because (a) activating K-Ras mutations are frequently found in pancreatic cancer and are also present in the pancreatic cancer cells used in this study (29)(30)(31), and (b) oncogenic K-Ras mutations frequently lead to constitutive activation of the downstream ERK-MAPK, which has been shown to be an effective antagonist of TGFh signaling (32).…”

FAK Is Required for TGFβ-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype

“…TGF␤ activates non-Smad signaling pathways, including MAP kinase cascades such as ras/MEK/ERK and JNK, which appear to be required for expression of target genes in a promoter-specific manner (Leask and Abraham, 2004;Javelaud and Mauviel, 2005). However, the mechanism underlying the activation of these ancillary non-Smad pathways is unclear.…”

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

“…Although Smads are well-characterized TGF-b signal transducers, TGF-b also signals through several Smadindependent pathways eventually resulting in complex cross-talk between the Smad and non-Smad, for example, mitogen-activated protein kinase (MAPK) signaling pathways (Derynck and Zhang, 2003;Javelaud and Mauviel, 2005). A central issue therefore relates to the contribution of Smad signaling to tumor suppression and the prometastatic function of TGF-b and how changes in the balance between TGF-b receptordependent Smad2/3 signaling and MAPK signaling affect tumor suppression.…”