ATHL1 Activators

ATHL1 can work through a variety of intracellular signaling pathways to promote its phosphorylation and subsequent activation. Forskolin directly raises cAMP levels within cells, which can activate protein kinase A (PKA). PKA is known to phosphorylate serine and threonine residues on its target proteins, and if ATHL1 contains such residues that are recognizable by PKA, forskolin can lead to its activation. Similarly, isoproterenol functions as a beta-adrenergic agonist, also raising cAMP levels and activating PKA, which can then target ATHL1. IBMX acts by inhibiting phosphodiesterases, thereby preventing the breakdown of cAMP and indirectly sustaining PKA activity, which again, could target ATHL1 for activation. In a different pathway, phorbol 12-myristate 13-acetate (PMA) activates protein kinase C (PKC), which may phosphorylate ATHL1 if it has PKC-specific phosphorylation sites. Bisindolylmaleimide I, while primarily a PKC inhibitor, under certain conditions can also activate PKC, which in turn may act on ATHL1.

Epidermal Growth Factor (EGF) stimulates its receptor, leading to a phosphorylation cascade through the MAPK/ERK pathway, which may include ATHL1 as a downstream target. Ionomycin increases intracellular calcium concentrations and can activate calcium/calmodulin-dependent protein kinases (CaMKs), which could phosphorylate ATHL1 if it is a substrate for these kinases. Anisomycin, by inhibiting protein synthesis, indirectly activates stress-activated protein kinases such as JNK, which may also target ATHL1. Calyculin A and Okadaic Acid both inhibit protein phosphatases PP1 and PP2A, leading to a general increase in protein phosphorylation within the cell; if ATHL1 is normally dephosphorylated by these phosphatases, these inhibitors can result in its activation by maintaining its phosphorylated state. Lastly, Spermine and Hydrogen Peroxide can affect ATHL1 through modulation of NMDA receptor activity and oxidative stress signaling, respectively, which can lead to the activation of various kinases that may target ATHL1.