The
tyrosine kinase Janus kinase 3 (JAK3) contributes to signaling regulating the proliferation and apoptosis of lymphocytes and
tumor cells. Replacement of
lysine by
alanine in the catalytic subunit yields the inactive (K851A)JAK3 mutant that underlies
severe combined immune deficiency. The gain-of-function mutation (A572V)JAK3 is found in acute megakaryoplastic
leukemia and
T cell lymphoma. The excessive nutrient demand of
tumor cells requires upregulation of transporters in the cell membrane including
peptide transporters PEPT1 and PEPT2. The carriers further accomplish intestinal
peptide transport. Little is known about signaling regulating
peptide transport. The present study explored whether PEPT1 and PEPT2 are upregulated by JAK3. PEPT1 or PEPT2 was expressed in Xenopus oocytes with or without additional expression of JAK3, and electrogenic
peptide (
glycine-
glycine) transport was determined by dual-
electrode voltage clamp. PEPT2-HA
membrane protein abundance was analyzed by chemiluminescence. Intestinal electrogenic
peptide transport was estimated from
peptide-induced current in Ussing chamber experiments. In PEPT1- and PEPT2-expressing oocytes, but not in water-injected oocytes, the
dipeptide gly-gly generated an inward current, which was significantly increased following coexpression of JAK3. The effect of JAK3 on PEPT1 was mimicked by (A568V)JAK3 but not by (K851A)JAK3. JAK3 increased maximal
peptide-induced current in PEPT1-expressing oocytes but rather decreased apparent affinity of the carrier. Coexpression of JAK3 enhanced the PEPT2-HA
protein abundance in the cell membrane. In JAK3- and PEPT1-expressing oocytes,
peptide-induced current was blunted by the JAK3 inhibitor
WHI-P154, 4-[(3'-bromo-4'-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (22 μM). In intestinal segments gly-gly generated a current which was significantly smaller in JAK3-deficient mice (jak3⁻/⁻) than in wild-type mice (jak3⁺/⁺). In conclusion, JAK3 is a powerful regulator of
peptide transporters PEPT1 and PEPT2.