Figure 4: Simplified RAGE signal transduction pathways. Note that the engagement of RAGE stimulates the activation of a diverse array of signaling cascades. These include mitogen activated protein kinases (MAPK), such as extracellular regulated (ERK)-1/2, p38 and c-Jun N-terminal kinase (JNK), Jak/STAT, phosphoinositol 3-kinase (PI3K), and members of the Rho GTPase signaling pathway (Cdc42 and Rac-1). Moreover, RAGE activation enhances the generation of reactive oxygen species (ROS) by activating NAD(P)H oxidase. Conversely, AGE may decrease NO availability by the decreased activity of NOS and by quenching NO. RAGE-dependent responses eventually converge to the activation of nuclear transcription factors (such as nuclear factor (NF-κB) and consequent target gene transcription (including endothelin-1, ICAM-1, E-selectin, and tissue factor) and ultimately triggering inflammatory pathways.