Smad2 transduces common signals from receptor serine–threonine and tyrosine kinases

Abstract

SMAD proteins mediate signals from receptor serine–threonine kinases (RSKs) of the TGF-β superfamily. We demonstrate here that HGF and EGF, which signal through RTKs, can also mediate SMAD-dependent reporter gene activation and induce rapid phosphorylation of endogenous SMAD proteins by kinase(s) downstream of MEK1. HGF induces phosphorylation and nuclear translocation of epitope-tagged Smad2 and a mutation that blocks TGF-β signaling also blocks HGF signal transduction. Smad2 may thus act as a common positive effector of TGF-β- and HGF-induced signals and serve to modulate cross talk between RTK and RSK signaling pathways.

Inhibition of the antiproliferative effect of TGFβ by EGF in primary human ovarian cancer cells

“…HGF and oncogenic ras have been shown to alter TGFb signaling in human breast cancer cells and mouse mammary epithelial cells, respectively (de Caestecker et al, 1998;Kretzschmar et al, 1999). In addition, IFNg can inhibit nuclear translocation of Smad3 in a mutant human fibrosarcoma cell line (Ulloa et al, 1999), which could interfere with TGFb transcriptional responses.…”

“…Numerous signaling pathways have been shown to converge with the TGFb signaling pathway to modulate its effects. Depending on the cell context, interferon gamma (IFNg), hepatocyte growth factor (HGF), epidermal growth factor (EGF) and oncogenic ras have all been shown to modulate TGFb signaling (de Caestecker et al, 1998;Kretzschmar et al, 1999;Ulloa et al, 1999;ten Dijke et al, 2000;Funaba et al, 2002).…”

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor

“…pT␤-RII contains 1,670 bp of the gene promoter of TGF-␤ receptor type 2 (T␤-RII) (4). cDNA expression plasmid pdn-T␤-RIIcDNA was a gift from Dr. Robert J. Lechleider (NCI) and contains cDNA encoding the dominant-negative form of T␤-RII (17). Semiconfluent HSCs in six-well cell culture plates were transiently transfected using LipofectAMINE reagent (Life Technologies, Grand Island, NY).…”

Genetic events and the role of TGFβ in epithelial tumour progression

“…Interestingly, there is increasing evidence for cross-talk between the TGF and the ras signalling pathway, with the observation that SMAD2 can be activated by the HGF-ras-MEK1-ERK1/2 pathway. 124 It has also been demonstrated that TGF can activate ras, and ERK1/2, and that this activity is essential for many of TGF 's actions, including negative growth control. 125,126 Certainly a dominant negative ras mutation can abrogate TGF effects, 127 but whether TGF and ras are on the same pathway or synergistically involved is not known.…”