Response by Student #1

20 May 2005

student number 1

HGF (RTK signaling molecule) and TGFbeta (Receptor S/T Kinase signaling molecule) are two important signaling molecules involved in cell invasion. Using primarily molecular techniques, Mori et al. studied exhaustively the crosstalk between HGF and TGF-b pathways via Smad signaling pathway. The generation of specific phospho-antibodies to the Linker and C-terminal regions of Smad2/3 is essential to this study. The authors convincingly demonstrated that HGF and TGF-b can activate the JNK pathways leading to phosphorylation of the Linker regions of Smad 2 and 3, which resulted in transactivation of PAI-1 gene leading to increased invasiveness of the cell. Additionally, HGF antagonize TGF-b anti- proliferative effects via inhibiting p15INK4B transcription, possibly due to decreased Smad3 C-terminal phosphorylation. These findings are supported by a series of inhibitor studies and luciferase assays.

I agree with the other students that this paper showed crosstalk between two very important pathways involved in tumor invasion process. Though, there is a lack of animal studies. I would like to see that the crosstalk described by the authors can be replicated in the mouse model by observing the increased invasiveness of transplanted tumor cells. However, this does not detract from the paper’s significance of demonstrating the crosstalk between RTK and receptor ser/thr kinase pathways.