Student #4 response to Student #7

20 May 2005

Student 4 Student 4

This paper describes the functional cross-talk between the TGF- beta receptor (a receptor serine/threonine kinase) and the hepatocyte growth factor (HGF) receptor (a receptor tyrosine kinase). Receptor-activated Smads (R-Smads) are phosphorylated by TGF-beta receptors and relay the receptor signal to the nucleus. Previous studies had implicated R-Smads in mediating the cross- talk between receptor serine kinases and receptor tyrosine kinases (Kretzschmar et al., 1997, 1999), but the precise molecular mechanisms and the functional consequences of this cross-talk were not clear.

The authors of this paper used phospho-specific antibodies to R- Smads to demonstrate cross-talk between TGF-beta/Smad and HGF/MAPK/JNK-mediated signals. They determined that either HGF or TGF-beta treatment could phosphorylate R-Smads, and together produced an additive effect. The additive effect was found to be due to additionally activated JNK, which directly phosphorylated R-Smads at linker regions. Simultaneous treatment with HGF and TGF-beta stimulated nuclear translocation of phosphorylated R-Smads, and increased the transcription of plasminogen activator inhibitor type 1 (PAI-1), which is involved in TGF-beta-induced cell invasion. The in vivo relevance of this effect was determined by measuring the invasive capacity induced by HGF and TGF-beta treatment, which was blocked by a JNK inhibitor. Thus, the authors were able to convincingly demonstrate the cross-talk between HGF and TGF-beta signaling pathways, producing a biologically relevant outcome.

I agree with the student’s choice of this paper as a good example of functional cross-talk between receptor serine/threonine kinase and receptor tyrosine kinase pathways. The use of phospho- specific antibodies as a tool to reveal specific molecular alterations and their consequences is particularly impressive. It is also interesting that, in this type of cross-talk, the two signaling pathways converge at a downstream cytoplasmic mediator, JNK, to produce an additive effect on PAI-1 transcription in the nucleus. This effect clearly has important implications in R-Smads-mediated signaling, and provides some insight into mechanisms of tumor invasion.

References:

Kretzschmar M, Doody J, Massague J. 1997. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389: 618-622 [PubMed] [Online Journal]

Kretzschmar M, Doody J, Massague J. 1999. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 13: 804-816 [PubMed] [Full Text in Virtual Journal] [Online Journal]