Integration of BMP, RTK, and Wnt Signaling Through Smad1 Phosphorylations

This chapter focuses on the integration of three different pathways, bone morphogenetic protein (BMP), RTK, and Wnt, at the level of a single transcription factor, Smad1, in the control of the differentiation of the ectoderm into neural or epidermal fates. It also discusses other situations in which Smads are utilized as a platform for the integration of different signaling pathways. During embryonic development, there are multiple situations in which the fibroblast growth factors (FGF)/mitogen-activated protein kinase (MAPK) pathway cross-talks with BMP signals. The MAPK-dependent phosphorylations of Smad1 are required for the inhibitory effects of BMP/Smads on androgen receptor function, and the integration of MAPK signals on Smad1 has a critical role in the androgen regulation of prostate cancer progression. An analogous mechanism of signal integration has been found for the transcription factors Smad2 and Smad3, which transduce signals of transforming growth factor β (TGFβ). The TGFβ growth factor pathway is a very important tumor suppressor in mammals. In Xenopus, the TGFβ molecule activin induces the expression of mesodermal genes in ectodermal cells, but this ability is lost after a certain point of development. This loss of competence correlated with the inability of Smad2 to accumulate in the nucleus, and mutation of conserved MAPK phosphorylation sites (SP) at the linker region of Smad2 prolongs the competence of cells to respond to activin by inducing mesodermal genes. TGFβs are also potent inhibitors of cell proliferation, and have crucial roles in the control of tumorigenesis. Certain types of cancer are resistant to the growth-inhibitory effects of TGFβ. In transformed cell lines with activated oncogenic Ras/MAPK signals, Smad2/3 protein displays elevated phosphorylation at their MAPK sites, which inhibits TGFβ-induced nuclear accumulation.