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VPAC1 Signaling Blocks Ikaros Degradation by a PKA Dependent Mechanism in Activated HuT‐78 Cells
Author(s) -
Van der Steen Travis,
Hermann Rebecca,
Benton Keith,
Dorsam Glenn
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.855.10
Subject(s) - forskolin , protein kinase a , microbiology and biotechnology , phosphorylation , vasoactive intestinal peptide , signal transduction , receptor , chemistry , biology , biochemistry , neuropeptide
Over 50,000 people in the U.S. die annually from Leukemia, and over half of these people have a mutation or splicing deregulation of the tumor suppressor Ikaros (IK) protein. The phosphorylation pattern of IK controls its DNA binding activity; through the antagonistic control of casein kinase II and protein phosphatase 1. IK also contains consensus sequences for other kinases such as PKA, PI3K, and cdk1. T cell activation shifts the equilibrium to favor hyperphosphorylation of IK thereby decreasing DNA binding and cell cycle entry. Vasoactive intestinal peptide receptor 1 (VPAC1) signaling opposes the activation of the T cell receptor by blocking T cell activation through a cAMP/PKA signaling cascade. We hypothesized that VIP/VPAC1 signaling regulates the phosphorylation of IK and impedes cell cycle entry. PMA/ionomycin activation of HuT 78 cells resulted in a decrease in IK protein, but was blocked with the addition of the VPAC1 ligand VIP (10 −8 M). When cells were treated with either an agonist (VIP 10–28 ) or a VIP+PKA inhibitor (H89) IK protein levels were reduced. When treated with forskolin to induce cAMP, no increase in IK was observed. These data suggest that IK is being regulated through a G protein coupled receptor by PKA in a cAMP independent mechanism. Research supported by NIH‐K01 1K01DK064828 and COBRE 2P20RR05566.