TI - Mycobacterium tuberculosis 6-kDa Early Secreted Antigenic Target ( ESAT-6 ) protein downregulates Lipopolysaccharide induced c-myc expression by modulating the Extracellular Signal Regulated Kinases 1/2 . AB - Background Mycobacterium tuberculosis ( Mtb ) causes death of 2-3 million people every year . The persistence of the pathogenic mycobacteria inside the macrophage occurs through modulation of host cell signaling which allows them , unlike the other non-pathogenic species , to survive inside the host . The secretory proteins of M.tuberculosis have gained attention in recent years both as vaccine candidates and diagnostic tools ; they target the immune system and trigger a putatively protective response ; however , they may also be involved in the clinical symptoms of the disease . Results Our studies showed that RD-1 -encoded secretory protein ESAT-6 is involved in modulation of the mitogen-activated protein ( MAP ) kinase -signaling pathway inside the macrophage . ESAT-6 induced PHOSphorylation of extracellular signal-regulated kinases 1/2 ( ERK1/2 ) in the cytoplasm but not in the nucleus , which normally is the case for MAP kinases . ESAT-6 also antagonized LPS -induced ERK1/2 PHOSphorylation in the nucleus . Stimulation of cells by ESAT-6 along with sodium orthovanadate ( a tyrosine phosphatase inhibitor ) restored phosphorylaTION of ERK1/2 in the nucleus , suggesting active dePHOSphorylation of ERK1/2 by some putative phosphatases in the nucleus . Further , ESAT-6 was found to down regulate the expression of LPS-inducible gene c-myc in an ERK1/2 -dependent manner . Conclusion This study showed the effect of secretory proteins of M.tuberculosis in the modulation of macrophage signaling pathways particularly ERK1/2 MAP kinase pathway . This modulation appears to be achieved by limiting the ERK1/2 activation in the nucleus which ultimately affects the macrophage gene expression . This could be a mechanism by which secretory proteins of Mtb might modulate gene expression inside the macrophages .