title: Stimulation of the glucose carrier SGLT1 by JAK2.
abstract: JAK2 (Janus kinase-2) overactivity contributes to survival of tumor cells and the (V617F)JAK2 mutant is found in the majority of myeloproliferative diseases. Tumor cell survival depends on availability of glucose. Concentrative cellular glucose uptake is accomplished by Na(+) coupled glucose transport through SGLT1 (SLC5A1), which may operate against a chemical glucose gradient and may thus be effective even at low extracellular glucose concentrations. The present study thus explored whether JAK2 activates SGLT1. To this end, SGLT1 was expressed in Xenopus oocytes with or without wild type JAK2, (V617F)JAK2 or inactive (K882E)JAK2 and electrogenic glucose transport determined by dual electrode voltage clamp experiments. In SGLT1-expressing oocytes but not in oocytes injected with water or JAK2 alone, the addition of glucose to the extracellular bath generated a current (I(g)), which was significantly increased following coexpression of JAK2 or (V617F)JAK2, but not by coexpression of (K882E)JAK2. Kinetic analysis revealed that coexpression of JAK2 enhanced the maximal transport rate without significantly modifying the affinity of the carrier. The stimulating effect of JAK2 expression was abrogated by preincubation with the JAK2 inhibitor AG490. Chemiluminescence analysis revealed that JAK2 enhanced the carrier protein abundance in the cell membrane. The decline of I(g) during inhibition of carrier insertion by brefeldin A was similar in the absence and presence of JAK2. Thus, JAK2 fosters insertion rather than inhibiting retrieval of carrier protein into the cell membrane. In conclusion, JAK2 upregulates SGLT1 activity which may play a role in the effect of JAK2 during ischemia and malignancy.
authors.affiliation: Department of Physiology I, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Hosseinzadeh
authors.forename: Shefalee K
authors.initials: SK
authors.lastname: Bhavsar
authors.forename: Manzar
authors.initials: M
authors.lastname: Shojaiefard
authors.forename: Ambrish
authors.initials: A
authors.lastname: Saxena
authors.forename: Katja
authors.initials: K
authors.lastname: Merches
authors.forename: Mentor
authors.initials: M
authors.lastname: Sopjani
authors.forename: Ioana
authors.initials: I
authors.lastname: Alesutan
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009865:Oocytes; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation; D014982:Xenopus laevis
chemical_list: D004791:Enzyme Inhibitors; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D003609:Dactinomycin; D020126:Brefeldin A; C507924:JAK2 protein, human; D053614:Janus Kinase 2