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Principles of Cell Signaling and Biological Consequences

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Final Forum: Student #7

10 May 2005

Student7 Student7

Mori, S., Matsuzaki, K., Yoshida, K., Furukawa, F., Tahashi, Y., Yamagata, H., Sekimoto, G., Seki, T., Matsui, H., Nishizawa, M., Fujisawa, J., and Okazaki, K. 2004. TGF-beta and HGF transmit signals through JNK- dependent Smad2/3 phosphorylation at the linker regions. Oncongene 23; 7416-7429. [PubMed] [Online Journal]

The various signaling pathways that can become activated in cells have very different consequences. Complicating this, many signaling pathways can interact with each other, and this also can lead to very different outcomes for the cells. The paper by Mori, et al, demonstrates cross-talk between two signaling pathways, and the functional consequences this can have on the cells. This paper deals with signaling cross-talk between TGF-b and HGF signaling pathways. TGF-b acts by binding to and activating specific transmembrane receptor serine/threonine kinases, such as TbR1. TbR1 then phosphorylates and activates R-Smads, which then couple to Smad4 and are translocated to the nucleus. In the nucleus, they can regulate transcription of specific genes. R-Smads have 2 conserved domains, which are connected by a middle linker region. R-Smads have two major phosphorylation sites: in the C-terminal domain and in the linker region, and there is evidence to suggest that phosphorylation of Smads is important for their function. EGF and HGF, on the other hand, signal through transmembrane receptor tyrosine kinases. The most prominent pathways involve signaling through MAPKs, including ERK, JNK/SAPK1, and p38, which in turn activate transcription factors. Recent data has reported Smad phosphorylation at linker regions upon HGF or EGF treatment, indicating that Smads play a role in mediating cross-talk between receptor serine kinases and receptor tyrosine kinases. In this paper, using specific phospho-antibodies to different Smad regions (C-terminal region vs. linker regions), the authors showed that HGF and TGF-b both activated the JNK pathway, inducing endogenous phosphorylation at the linker regions of Smad 2 and 3. This suggests the linker regions are common phosphorylation sites for HGF and TGF-b signaling pathways. Smad3 phosphorylated by HGF increased its association with Smad4 and its translocation to the nucleus, which shows a biological function for linker region phosphorylation. This translocation can be blocked with an inhibitor of JNK. Treating the cells with HGF and TGF-b, the authors saw an increase in cell invasiveness, which was blocked with a JNK inhibitor. Because JNK can phosphorylate Smad3, it suggests that linker region phosphorylation participates in the invasive ability of the cells. Although data has suggested that cross-talk between MAPK-mediated signals and Smads occurs in the nucleus, the data in this paper suggests that cross-talk can occur at the cytoplasmic level, with JNK directly phosphorylating R-Smads, leading to transcriptional activation of the PAI- 1 gene in the nucleus. HGF can also inhibit the anti-proliferative effect of TGF-b, possibly due to decreased expression of p15INK4B, which may be due to decreasing C-terminal phosphorylation of Smad3 (HGF decreases C- terminal phosphorylation of Smad3). Translocation of Smad3 to the nucleus upon HGF treatment could prevent C-terminal phosphorylation. This paper shows that HGF cross-talk with the TGF-b pathway changes the phosphorylation state and cellular localization of R-Smads and, as a result, cells may no longer respond in the same manner to TGF-b. This could function, for example, in causing TGF-b to act as a tumor promoter instead of a tumor suppressor. More work must be done to elucidate the molecular mechanisms of this signaling cross-talk, but this study is important because it shows that signaling pathway cross-talk can have important functional consequences for the cell.

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