Stimulation of the glucose carrier SGLT1 by JAK2

JAK2 (Janus kinase-2) overactivity contributes to survival of tumor cells and the V617FJAK2 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, V617FJAK2 or inactive K882EJAK2 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 (Ig), which was significantly increased following coexpression of JAK2 or V617FJAK2, but not by coexpression of K882EJAK2. 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 Ig 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.

► The glucose carrier SGLT1 is upregulated by Janus kinase-2 JAK2 but not inactive K882EJAK2.
► The V617FJAK2 mutant, causing myeloproliferative disease, is more effective.
► SGLT1 is downregulated by JAK2 inhibitor AG490.
► JAK2 is effective by enhancing SGLT1 protein insertion into the cell membrane.
► SGLT1 thus contributes to glucose uptake into V617FJAK2 + SGLT1 expressing tumor cells.