Posttranslational Regulation of the Tumor‐Suppressor Ikaros by Vasoactive Intestinal Peptide Receptor 1 in Human HuT 78 Cells

Abstract

Ikaros (IK) is a krupple‐like zinc finger and master regulator of lymphopoesis. Mutations to the IK DNA binding domain result in T cell leukemia. The phosphorylated posttranslational modifications of IK have been shown to be regulated by casein kinase II (CKII) throughout the primary sequence. Putative consensus sequences for additional kinases such as GSK3, Cdk, CaMKII, and PKA have been identified. Hyperphosphorylation of IK reduces its DNA binding affinity and mediates G1/S transition. Vasoactive intestinal peptide/pituitary adenylyl cyclase activating peptide receptor 1 (VPAC1) is a G protein coupled receptor that negatively regulates T cell receptor (TCR) activation through a cAMP/PKA signaling dependent pathway when bound by its ligand, vasoactive intestinal peptide (VIP). Our hypothesis is that VIP/VPAC1 signaling suppresses CKII phosphorylation of IK in a PKA dependent mechanism. Upon T cell activation, a new immunoreactive pool of IK was detected, and VIP (10‐8M) ablated the detection of this hyperphosphorylated species. We conclude that VIP/VPAC1 signaling may block the immunoreactive pool of a certain hyperphosphorylated IK species thereby negatively regulating T cell activation. Research supported by NIH‐K01 1K01DK064828 and COBRE 2P20RR05566.