Smad2/3 and Smad4 are direct mediators of TGF b signalling and there is now ample evidence to nothing suggest that Smad2 and Smad3 have distinct and non overlap ping roles in TGF b signalling and that these differ in epithelial cells and fibroblasts ]. However, relatively few studies on the roles of Smad2 and Smad3 in TGF b signalling have been performed in human epithelial cells from which most cancers arise. Moreover, it remained a mystery why TGF b can induce different functions, such as growth arrest and epithelial to mesenchymal transition, in the same cell lines, even though both play opposing roles in tumourigenesis. The mechanisms for the selec tive activation of Smad2 versus Smad3 are largely unknown but can principally occur at the level of the TbRs, nuclear import and export, protein turnover, and/or at the transcriptional level.

Alternatively, Smad2 versus Smad3 responses may be selected by post translational modifications such as differential phosphorylation at the TbR complex. It is possible that the availability of other factors such as co repres sors and co activators determine which response is mediated by Smad3 and Smad2. Since strategies for therapeutic targeting Inhibitors,Modulators,Libraries of the TGF b signalling pathway are being pursued, revealing the identity of factors that modulate the relative activation of Smad2 or Smad3 in the TGF b response may provide target for more effective strategies for cancer therapy. Rac1 belongs to the Rho family of small GTPases and has been implicated in the organization of the actin cytoskeleton, the formation of lamellopodia and focal adhesions, and in endocytic Inhibitors,Modulators,Libraries vesicle trafficking and recep tor endocytosis.

Rac1 can also drive cell proliferation and protect cells from apoptosis through its ability to activate extracellular signal regulated kinases, phosphati dylinositol 3 kinase, Inhibitors,Modulators,Libraries and the transcription factor NF B ]. Activated Rac1 acts syner gistically with ligand activated epidermal growth factor receptor Inhibitors,Modulators,Libraries to stimulate pancreatic tumour cell proliferation through cyclin D1 upregulation. Rac1 has a critical role in cell migration, and in the invasive, and metastatic behavior of cancer cells. More over, Rac1 function Inhibitors,Modulators,Libraries is required for oncogenic K Ras tumourigenesis and proliferation. Activation of Rac1 is accompanied by its rapid translocation from the cyto sol to the cell membrane, where it exerts part of its effects as an essential subunit of the reactive oxygen spe cies producing enzyme NAD H oxidase.

In PDAC dysregulated expression of Rac1 was observed in the tumour cell compartment, along with high activ ity of Vav1, a guanine exchange factor, which exhi bits a particularly strong guanine exchange activity EPZ-5676 leukemia for Rac1. Also TGF b and Rac1 signalling exert antago nistic roles in tumour cell proliferation but share com mon nuclear targets such as cyclin D1 and p21WAF1.