Signaling mechanisms for the activation of HAT and HDAC

Signaling mechanisms for the activation of HAT and HDAC. (a) Pathways for the activation of CBP HAT in neurons. Activity-dependent activation of CBP depends on CAMK-IV-dependent phosphorylation on Ser 301. CBP is also activated by elevation in cAMP level. Ethanol, for example, phosphorylates adenosine A2 receptor by blocking adenosine uptake and its buildup. Subsequently, cAMP level is increased by adenylyl cyclase. cAMP-mediated activation of CBP is dependent on type-I PKA-mediated phosphorylation. Growth factors (like NGF) can trigger CBP phosphorylation via p42/p44 MAPK, which has been shown to interact directly with CBP. NGF can also trigger Ras pathway to mediate phosphorylation of 90 kDa ribosomal S6 kinase (RSK), which binds to CBP and canalizes expression of genes dependent on Ras pathway. However, this interaction inhibits expression of genes with CRE elements in PC12 cells. (b and c) Different modus operandi of class-I and class-II HDACs. HDAC1, HDAC2 and HDAC3 are phosphorylated by a distinct set of kinases. Once phosphorylated, they assemble into greater repressive complexes showing greater enzymatic activity and inhibit gene expression. In contrast, phosphorylation of HDAC8 decreases its enzymatic activity. Among all the represented HDAC complexes, the HDAC1/2-Co-REST complex is neuron specific. On the other hand, as shown in myoblasts, several type-II HDACs, once phosphorylated, are exported from the nucleus in complex with 14-3-3 proteins. The binding of HDACs with 14-3-3 proteins results in their release from the repression complex, allowing expression of the gene. Whether similar mechanisms are applicable to neurons is yet to be verified. Blue connectors represent kinase activity

Publication

HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. () RN Saha, et al. Cell Death Differ. ;13(4):539-550. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions