This is a well-known pathway, with the most important proteins involved described and characterized.
NFATC are activated by stimulation of receptors coupled to calcium mobilization (vg. TcR) and certain receptors coupled to certain heterotrimeric G proteins (vg. muscarinic receptor). This stimulus induces activation of many intracellular enzymes, including the calcium and calmodulin-dependent phosphatase calcineurin, a major upstream regulator of NFAT protein. NFATs' targets are genes that code for transcription factors, signalling proteins, cytokines, cell surface receptors and other effector proteins.
In their activation by calcineurin, three main steps have been defined: dephosphorylation, nuclear translocation and increase in their affinity for DNA. In resting cells NFATs are phosphorylated and localized in cytoplasm, while after being stimulated, they are dephosphorylated by calcineurin, their NLS (nuclear localization sequence) is exposed and they are translocated to the nucleus, showing increased affinity for DNA.
NFkB is normally retained in the cytoplasm by the inhibitor IkB family that includes IkBalpha, beta, and gamma.
The most commonly studied pathway of NFkB activation involves the phosphorylation of IkBalpha on serine residues 32 and 36 by the IkB-kinase (IKK) complex. This leads to ubiquitination and degradation of IkB proteins, which unmasks a nuclear target sequence on the NFkB molecule and results in the translocation of NFkB from the cytoplasm to the nucleus as an active transcription factor.
An alternative mechanism is associated with the dissociation of NFkB from IkBalpha without proteolytic degradation, which may involve the tyrosine phosphorylation of IkBalpha.
More investigation is needed to clarify the role that NFAT5 plays in the cell.