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Stimulation of the Na(+)-coupled glucose transporter SGLT1 by B-RAF

Tatsiana Pakladok1, Zohreh Hosseinzadeh, Ioana Alesutan

  • 1Department of Physiology I, University of Tübingen, Germany.

Biochemical and Biophysical Research Communications
|September 27, 2012
PubMed

Insights

Gain of function mutations in B-RAF (B-Rapidly Accelerated Fibrosarcoma) protein kinase can promote tumor growth. This study shows B-RAF upregulates the Na(+)-coupled glucose transporter SGLT1, enhancing glucose uptake in tumor cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Gain-of-function mutations in B-RAF serine/threonine protein kinase are implicated in tumor development.
  • Tumor cells rely on glucose for energy, necessitating efficient glucose uptake mechanisms.
  • The Na(+)-coupled glucose transporter SGLT1 facilitates concentrative glucose uptake, even at low extracellular glucose levels, and is present in several tumor types.

Purpose of the Study:

  • To investigate whether B-RAF activation influences the activity of the SGLT1 glucose transporter.
  • To determine the mechanism by which B-RAF might affect SGLT1 function.

Main Methods:

  • SGLT1 was expressed in Xenopus oocytes, with or without coexpression of wild-type B-RAF.
  • Electrogenic glucose transport was measured using dual electrode voltage clamp.
  • Protein abundance in the cell membrane was assessed via chemiluminescence and confocal microscopy.
  • The role of vesicle insertion was examined using Brefeldin A, an inhibitor of vesicle transport.

Main Results:

  • Coexpression of B-RAF significantly increased glucose-induced current (I(g)) in SGLT1-expressing oocytes.
  • Kinetic analysis revealed that B-RAF enhances the maximal transport rate of SGLT1 without altering its glucose affinity.
  • B-RAF increased SGLT1 protein levels in the cell membrane.
  • Inhibition of vesicle insertion with Brefeldin A led to a greater decline in I(g) in oocytes expressing both SGLT1 and B-RAF, suggesting B-RAF-mediated upregulation involves membrane insertion.

Conclusions:

  • B-RAF upregulates SGLT1 activity, thereby increasing glucose uptake.
  • This upregulation mechanism requires the insertion of SGLT1 into the cell membrane via vesicles.
  • Targeting the B-RAF/SGLT1 interaction could offer a strategy for managing B-RAF-driven tumors.

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