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J Membr Biol
2013 Dec 01;24612:885-92. doi: 10.1007/s00232-013-9582-3.
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Effect of Janus kinase 3 on the peptide transporters PEPT1 and PEPT2.
Warsi J
,
Hosseinzadeh Z
,
Dong L
,
Pakladok T
,
Umbach AT
,
Bhavsar SK
,
Shumilina E
,
Lang F
.
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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.
Alesutan,
Upregulation of Na-coupled glucose transporter SGLT1 by Tau tubulin kinase 2.
2012, Pubmed,
Xenbase
Alesutan,
Upregulation of Na-coupled glucose transporter SGLT1 by Tau tubulin kinase 2.
2012,
Pubmed
,
Xenbase
Alteheld,
Alanylglutamine dipeptide and growth hormone maintain PepT1-mediated transport in oxidatively stressed Caco-2 cells.
2005,
Pubmed
Ananthakrishnan,
JAK-STAT pathway in cardiac ischemic stress.
2005,
Pubmed
Bhavsar,
Janus kinase 3 is expressed in erythrocytes, phosphorylated upon energy depletion and involved in the regulation of suicidal erythrocyte death.
2011,
Pubmed
Boehmer,
The peptide transporter PEPT2 is targeted by the protein kinase SGK1 and the scaffold protein NHERF2.
2008,
Pubmed
,
Xenbase
Brandsch,
Transport of drugs by proton-coupled peptide transporters: pearls and pitfalls.
2009,
Pubmed
Candotti,
Structural and functional basis for JAK3-deficient severe combined immunodeficiency.
1997,
Pubmed
Chen,
Complex effects of naturally occurring mutations in the JAK3 pseudokinase domain: evidence for interactions between the kinase and pseudokinase domains.
2000,
Pubmed
Dërmaku-Sopjani,
Downregulation of NaPi-IIa and NaPi-IIb Na-coupled phosphate transporters by coexpression of Klotho.
2011,
Pubmed
,
Xenbase
de Totero,
The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways.
2008,
Pubmed
Foley,
Bioavailability through PepT1: the role of computer modelling in intelligent drug design.
2010,
Pubmed
Ghoreschi,
Janus kinases in immune cell signaling.
2009,
Pubmed
Gonzalez,
An oligopeptide transporter is expressed at high levels in the pancreatic carcinoma cell lines AsPc-1 and Capan-2.
1998,
Pubmed
Haan,
Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors.
2011,
Pubmed
Henrion,
Overlapping cardiac phenotype associated with a familial mutation in the voltage sensor of the KCNQ1 channel.
2012,
Pubmed
,
Xenbase
Hosseinzadeh,
Regulation of the glutamate transporters by JAK2.
2011,
Pubmed
,
Xenbase
Hosseinzadeh,
Stimulation of the glucose carrier SGLT1 by JAK2.
2011,
Pubmed
,
Xenbase
Hosseinzadeh,
Upregulation of peptide transporters PEPT1 and PEPT2 by Janus kinase JAK2.
2013,
Pubmed
,
Xenbase
Hosseinzadeh,
Downregulation of ClC-2 by JAK2.
2012,
Pubmed
,
Xenbase
Ingersoll,
The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease.
2012,
Pubmed
Inoue,
Regulation of human peptide transporter 1 (PEPT1) in gastric cancer cells by anticancer drugs.
2005,
Pubmed
Kamal,
Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity.
2008,
Pubmed
Kim,
MS-1020 is a novel small molecule that selectively inhibits JAK3 activity.
2010,
Pubmed
Koo,
Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.
2012,
Pubmed
Malinge,
Activating mutations in human acute megakaryoblastic leukemia.
2008,
Pubmed
Meredith,
Review. The mammalian proton-coupled peptide cotransporter PepT1: sitting on the transporter-channel fence?
2009,
Pubmed
,
Xenbase
Mitsuoka,
Inhibition of oligopeptide transporter suppress growth of human pancreatic cancer cells.
2010,
Pubmed
Nagel,
Microarray analysis of the global gene expression profile following hypothermia and transient focal cerebral ischemia.
2012,
Pubmed
Nakamura,
Pharmacogenetics of intestinal absorption.
2008,
Pubmed
Nakayama,
BLNK suppresses pre-B-cell leukemogenesis through inhibition of JAK3.
2009,
Pubmed
Newstead,
Towards a structural understanding of drug and peptide transport within the proton-dependent oligopeptide transporter (POT) family.
2011,
Pubmed
Notarangelo,
Of genes and phenotypes: the immunological and molecular spectrum of combined immune deficiency. Defects of the gamma(c)-JAK3 signaling pathway as a model.
2000,
Pubmed
Pathare,
OSR1-sensitive renal tubular phosphate reabsorption.
2012,
Pubmed
,
Xenbase
Pesu,
Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs.
2005,
Pubmed
Pieri,
The apical (hPepT1) and basolateral peptide transport systems of Caco-2 cells are regulated by AMP-activated protein kinase.
2010,
Pubmed
Rexhepaj,
PI3 kinase and PDK1 in the regulation of the electrogenic intestinal dipeptide transport.
2010,
Pubmed
Rubio-Aliaga,
Peptide transporters and their roles in physiological processes and drug disposition.
2008,
Pubmed
Strutz-Seebohm,
Structural basis of slow activation gating in the cardiac I Ks channel complex.
2011,
Pubmed
,
Xenbase
Tai,
Expression profile and functional activity of peptide transporters in prostate cancer cells.
2013,
Pubmed
Thomis,
T cells from Jak3-deficient mice have intact TCR signaling, but increased apoptosis.
1997,
Pubmed
Tsume,
Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: increased transporter affinity and metabolic stability.
2008,
Pubmed
Uckun,
Targeting JAK3 tyrosine kinase-linked signal transduction pathways with rationally-designed inhibitors.
2007,
Pubmed
Vijayakrishnan,
Treating inflammation with the Janus kinase inhibitor CP-690,550.
2011,
Pubmed
Walters,
Activating alleles of JAK3 in acute megakaryoblastic leukemia.
2006,
Pubmed
Wang,
Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells.
2008,
Pubmed
Yarandi,
Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation.
2011,
Pubmed
