WDR66 Activators

Chemical activators of WDR66 can engage distinct cellular pathways to facilitate its activation. Forskolin, through the activation of adenylate cyclase, leads to an increase in cAMP levels within the cell. The rise in cAMP can activate protein kinase A (PKA), which in turn is capable of phosphorylating WDR66, thus driving its activation. Similarly, Phorbol 12-myristate 13-acetate (PMA) activates protein kinase C (PKC), which is known to phosphorylate serine and threonine residues on target proteins. The phosphorylation by PKC can serve to activate WDR66. Ionomycin, by increasing intracellular calcium levels, can activate calcium/calmodulin-dependent protein kinases, which may phosphorylate WDR66, leading to its activation. A parallel mechanism is induced by A23187 (Calcimycin), which also raises cytosolic calcium levels and, thus, can activate WDR66 through calcium-dependent phosphorylation.

The chemicals Spermine NONOate and Zaprinast work through modulation of cyclic nucleotide levels; Spermine NONOate donates nitric oxide that increases cGMP levels, activating cGMP-dependent protein kinase (PKG), which can then phosphorylate and activate WDR66. Zaprinast, by inhibiting phosphodiesterase 5, elevates cGMP levels, which can enhance PKG activity and subsequently activate WDR66. Calyculin A and Okadaic acid, both inhibitors of protein phosphatases PP1 and PP2A, can lead to a net increase in the phosphorylation state of cellular proteins, including WDR66, thereby promoting its activation. Epigallocatechin gallate (EGCG) activates AMP-activated protein kinase (AMPK), which can then phosphorylate WDR66 directly or through downstream effector proteins, leading to its activation. Anisomycin, by activating c-Jun N-terminal kinase (JNK), can phosphorylate WDR66 as part of the cellular response to stress, leading to its activation. Lastly, LY294002, by inhibiting phosphoinositide 3-kinases (PI3K), can indirectly initiate a compensatory activation of AKT, which may then phosphorylate and activate WDR66. H-89, while primarily known as a PKA inhibitor, may lead to the compensatory upregulation of other kinases, which could then phosphorylate and activate WDR66.