Interplay between TGF-β signaling and receptor tyrosine kinases in tumor development

Transforming growth factor-β(TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in various diseases including tumor formation.Receptor tyrosine kinases(RTKs), such as epidermal growth factor receptor(EGFR), fibroblast growth factor receptor(FGFR),vascular endothelial growth factor receptor(VEGFR) and platelet-derived growth factor receptor(PDGFR), also play key roles in the development and progression of many types of tumors. It has been realized that TGF-β signaling and RTK pathways interact with each other and their interplay is important for cancer development. They are mutually regulated and cooperatively modulate cell survival and migration, epithelial-mesenchymal transition, and tumor microenvironment to accelerate tumorigenesis and tumor metastasis. RTKs can modulate Smad-dependent transcription or cooperate with TGF-β to potentiate its oncogenic activity,while TGF-β signaling can in turn control RTK signaling by regulating their activities or expression. This review summarizes current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development.

ALK-mediated Tyr95 phosphorylation of Smad4 impairs its transcription activity and the tumor suppressive activity of TGF-β

Transforming growth factorβ(TGF-β)regulates various physiological processes such as cell proliferation,differentiation,morphogenesis,andt tissue homeostasis and regeneration.The deregulation of these processes leads to many types of human diseases such as cancer(Massague,2008).TGF-βsignaling is initiated upon active TGF-βdimer binding to the type II receptor TβRII and the type I receptor TβRI on cell surface.