Upregulation of Peptide Transporters PEPT1 and PEPT2 by Janus Kinase JAK2

Background/Aims: Janus-activated kinase-2 JAK2 participates in the signaling of several hormones including growth hormone, fosters tumor growth and modifies the activity of several Na+ coupled nutrient transporters. Peptide uptake into intestinal and tumor cells is accomplished by electrogenic peptide transporters PEPT1 and PEPT2. The present study thus explored whether JAK2 contributes to the regulation of PEPT1 and PEPT2 activity. Methods: cRNA encoding either PEPT1 or PEPT2 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, constitutively active (V617F)JAK2 or inactive (K882E)JAK2. The current created by the dipeptide glycine-glycine (Igly-gly) was determined by dual electrode voltage clamp and taken as measure for electrogenic peptide transport. Results: No appreciable Igly-gly was observed in water injected oocytes. In PEPT1 or PEPT2 expressing oocytes Igly-gly was significantly increased by additional coexpression of JAK2. As shown in PEPT1 expressing oocytes, Igly-gly was increased by coexpression of (V617F)JAK2, but not of (K882E)JAK2. JAK2 enhanced maximal Igly-gly without significantly modifying the concentration required for halfmaximal Igly-gly (K-M). Following disruption of carrier insertion with brefeldin A (5 mu M) Igly-gly declined similarly fast in Xenopus oocytes expressing PEPT1 with JAK2 and in Xenopus oocytes expressing PEPT1 alone. In oocytes expressing both, PEPT1 and (V617F)JAK2, Igly-gly was gradually decreased by JAK2 inhibitor AG490 (40 mu M). According to Ussing chamber experiments pharmacological JAK2 inhibition similarly decreased Igly-gly in mouse intestine. Conclusion: Regulation of the peptide transporters PEPT1 and PEPT2 does involve the Janus-activated kinase-2 JAK2. Copyright (C) 2013 S. Karger AG, Basel