In addition, DR0053 was highly produced after ��-radiation, and the dr0053 mutant displayed increased sensitivity to ��- radiation and MMC exposure. Taken together, these observations suggest that DR0053 is necessary to cope with the stress generated from these damaging agents. DR0053 is a probable substrate protein for BY-kinase of D. radiodurans. BY-kinases, which phosphorylate tyrosine residues on their substrate proteins, are involved in several cellular processes, including the heat shock response, DNA replication, and the cell cycle. However, they have been best characterized for their involvement in the production of exopolysaccharide . A sequence homology search using the PSI-BLAST tool revealed that DRA0033, denoted ��ExoP-related protein��, is homologous to PtkA and is MK-4827 PARP inhibitor located within the gene cluster involved in EPS biosynthesis in D. radiodurans. This is consistent with the fact that most experimentally validated BY-kinases are encoded by genes located in large operons involved in EPS biosynthesis and export. Although further research is warranted to identify a link between DR0053 and DRA0033, the location of DRA0033 provides a clue to the role of DR0053. Transforming growth factor-beta plays a dual role in melanoma, mediating tumor GDC-0941 clinical trial suppressive activities at early stages and prooncogenic activities at later stages of tumor progression. At the cell surface, TGF-b binds a complex of transmembrane receptor serine/threonine kinases and induces transphosphorylation and activation of the type I receptor by the type II receptor kinase. The activated type I receptor phosphorylates the downstream effectors Smad2 and Smad3 at C-terminal serines. Smad2 and Smad3 then associate with a common Smad4, and these activated complexes translocate into the nucleus, where they regulate transcription of target genes. The linker region of Smad2 and Smad3, between the MH1 and MH2 domains, has been shown to be the target of mitogen-activated protein kinases, including ERK, JNK and p38, cyclindependent kinases and glycogen synthase kinase 3b. Four sites within the linker region have been the focus of several studies: Threonine 220 and Serines 245, 250 and 255 for Smad2; Threonine 179 and Serines 204, 208 and 213 for Smad3. Although it is now clear that modulation of Smad activity occurs through this linker region, the exact consequences of linker phosphorylation of Smad2 and Smad3 on their transcriptional activity is certainly linked to Smadinteracting partners and the complexity of the promoters. From studies on epithelial cells, carcinomas, gliomas and melanomas, it appears that Smads, through their linker domain, are at the point of convergence of major cellular signaling pathways, involving ERK, JNK, p38, CDK, GSK3b. GSK3b activity is negatively regulated upon AKT phosphorylation on serine 9. Therefore, it appeared that a crosstalk between the TGFb signaling pathway and the AKT/GSK3b arm could take place through the Smad phosphorylation at their linker domain.