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You can Never have too many kinases: The Sodium Hydrogen Exchanger Isoform 1 Regulation by Phosphorylation

Mark A Wallert, Dan Hastle, Clarice H. Wallert, Wayne Taylor Cottle and Joseph J. Provost*

Regulation of Na+-H+ exchanger isoform 1 (NHE1) activity is a dynamic, integrated system demonstrating the complexity of kinase signaling. Studies of NHE1 have described 22 confirmed and putative phosphorylation sites on the cytoplasmic domain regulated by 12 protein kinases. However the final number of sites and the impact of these sites remains unclear. By identifying the Rock phosphorylation site and its role in regulating NHE1 activity, we began to understand the functional interplay between the RhoA/Rock and Rsk/Erk pathways. This demonstrates the need to have a complete and comprehensive understanding of the relationship between each kinase involved in NHE1 modification for a true understanding of the exchanger’s role in the control of cellular biological activity. By observing how the Rock phosphorylation site impacts cellular proliferation, it was demonstrated that Rock activity is only partially responsible for NHE1’s impact on biological activity. Furthermore, data presented here shows that Rock activity is involved in both α1-adrenergic (Phenylephrine) and LPA signaling but not PDGF activation of NHE1 transport activity suggesting that growth factor signaling does not require Rock, yet the kinase is essential in the effects of GPCR pathways. Of particular interest and adding to the complexity of kinase signaling, Pyk2 activity has been found to have an inhibitory effect on NHE1. These data demonstrate an uncertainty in the exact role that different kinases play in the regulation of NHE1 function, yet succeeds in providing evidence of the intricacy of phosphorylation organization and a need for further elucidation of the interplay between phosphorylation sites. Overall, the pivotal role of NHE1 in disease establishment and progression creates a solid argument for continued efforts in understanding its regulation.