The crosstalk of RAS with the TGF-β family during carcinoma progression and its implications for targeted cancer therapy

Abstract

Both RAS and transforming growth factor (TGF)-β signaling cascades are central in tumorigenesis and show synergisms depending on tumor stage and tissue context. In this review we focus on the interaction of RAS subeffector proteins with signaling components of the TGF-β family including those of TGF-βs, activins and bone morphogenic proteins. Compelling evidence indicates that RAS signaling is essentially involved in the switch from tumor-suppressive to tumor-promoting functions of the TGF-β family leading to enhanced cancer growth and metastatic dissemination of primary tumors. Thus, the interface of these signaling cascades is considered as a promising target for the development of novel cancer therapeutics. The current pharmacological anti-cancer concepts combating the molecular cooperation between RAS and TGF-β family signaling during carcinoma progression are critically discussed.

Fig. (1)

Collaboration between RAS signaling and the TGF-β/activin/BMP pathways. Upon binding of cytokines of the TGF-β/activin/BMP family to TGF-β/activin/BMP-specific type II receptors, heterodimerization with type I receptors of activin receptor-like kinases (ALKs) occurs. Type I receptors further phosphorylate receptor-regulated (R)-Smads (Smad1, Smad2, Smad3, Smad5 and Smad8) and cause their nuclear translocation together with the common-partner (Co-)Smad4. In the nucleus, Smad complexes bind to their respective response elements in target gene promoters and act as transcription factors which modulate gene expression. TGF-β/activin/BMP signaling is controlled at the level of (i) ligand mobilization and binding, (ii) receptor heterodimerization and activation, (iii) phosphorylation of R-Smads and nuclear shuttling of R/Co-Smad as well as (iv) Smad-dependent transcription complexes. The crosstalk of RAS and TGF-β family proteins involves (i) modulation of RAS subeffector proteins by TGF-β family receptors, and (ii) the interference of RAS signaling components either with the activation and nuclear translocation of Smad effectors or with Smad-dependent regulation of transcription.

Fig. (2)

Schematic domain structure and phosphorylation pattern of Smad proteins. Smads consist of the N-terminal Mad-homology (MH) 1 region and the C-terminal MH2 domain which is joined by the linker region. The MH1 region is required for DNA-binding and contains a nuclear localization signal (NLS), whereas the MH2 region is involved in protein-protein interactions required for regulation of transcription. In Smad2, direct binding of DNA is blocked by an additional sequence in the MH1 domain. ALK1-7 phosphorylate R-Smads at the two serine residues of the C-terminal SXS motif, which generally leads to hetero-oligomerization with Smad4 and nuclear translocation. Several RAS-regulated kinases such as ERK, JNK and p38MAPK phosphorylate Smad proteins predominantly in the linker region and modulate their activity.