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FLASH GENE
Symbol SLC2A4 contributors: mct - updated : 22-06-2018
HGNC name solute carrier family 2 (facilitated glucose transporter), member 4
HGNC id 11009
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • twelve putative transmembrane segments (12TM)
  • intracellular N and C termini
  • a large extracellular loop, with first intracellular loop of GLUT4 containing the retention motif WLGRK, in which W105 plays a prominent role
  • a glycosylation site between TM1 and 2
  • a small and a large intracellular loops, respectively between TM2 and 3 and TM8 and 9, both with the conserved RXGRR motif
  • HOMOLOGY
    Homologene
    FAMILY
  • major facilitator superfamily
  • sugar transporter family
  • glucose transporter subfamily
  • CATEGORY transport carrier
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic,vesicle
    text
  • stimulation of glucose uptake by insulin requires translocation of SLC24A to intracellular storage sites to cell surface
  • AXIN1, TNKS2 and KIF3A are co-localized with SLC2A4 on the trans-Golgi network
  • reduced SLC2A4 translocation from intracellular storage compartments to the plasma membrane is a cause of peripheral insulin resistance
  • basic FUNCTION
  • facilitated glucose transporter
  • mediating insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane
  • specific role in glucose homeostasis in conjunction with LNPEP
  • mediating the postprandial blood glucose clearance
  • role for LNPEP and SLC2A4 in activity-dependent glucose uptake in hippocampal neurones
  • dynamically retained through idle cycling among selective intracellular compartments, from whence it undergoes slow recycling to the plasma membrane (PM)
  • cardiac glucose utilization is regulated by reversible translocation of the glucose transporter SLC2A4 from intracellular stores to the plasma membrane
  • facilitates insulin-stimulated glucose uptake in peripheral tissues including adipose, muscle, and heart
  • SLC2A4 and SLC2A8 trafficking is impaired in the diabetic atria and rescued by insulin treatment
  • plays a major role in glucose homeostasis and is efficiently retained intracellularly in adipocytes and myocytes
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS facilitated diffusion transport
    PATHWAY
    metabolism carbohydrate
    signaling
    a component
  • C-ter is required for protein targeting to the perinuclear donor membranes but not to the insulin-responsive vesicles
  • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • CaČ&
  • 8314; signals promote SLC2A4 exocytosis and reduce its endocytosis in muscle cells
    protein
  • SLC2A4RG and MEF2A to activate SLC2A4 transcription
  • interacting with SGK1 (stimulates glucose transport by enhancing the abundance of SLC2A4 in the cell membrane at least in part via direct SLC2A4 phosphorylation)
  • interacting with TBC1D4
  • interacting with VAMP4, VAMP8, VAMP2 (requirement for VAMP4 for the initial biosynthetic entry of SLC2A4 from the Golgi apparatus into the insulin-responsive vesicle compartment, VAMP8, for plasma membrane endocytosis and VAMP2 for sorting to the specialized insulin-responsive compartment after plasma membrane endocytosis)
  • ARFRP1 appears to be involved in sorting of SLC2A4
  • AXIN1 interacts with the ADP-ribosylase tankyrase 2 (TNKS2) and the kinesin motor protein KIF3A, forming a ternary complex crucial for SLC2A4 translocation in response to insulin
  • RAB10 is likely involved in insulin-stimulated translocation of SLC2A4 storage vesicle (GSV) to the Plasma membrane, with RAB14 involved in insulin-stimulated translocation of SLC2A4-containing endosome
  • insulin promotes SLC2A4 exocytosis by regulating SLC2A4 vesicle arrival at the cell periphery and its subsequent tethering, docking, and fusion with the plasma membrane
  • interaction of vesicular MYO1C with cortical actin filaments is required for insulin-mediated tethering of SLC2A4 vesicles and for efficient SLC2A4 surface delivery in muscle cells
  • VAMP3, is able to protect insulin-stimulated SLC2A4 translocation during early stages of diet-induced insulin resistance and preserves normal CD36 distribution
  • DNAJC5 is involved in insulin resistance by interrupting SLC2A4 vesicle docking with the plasma membrane
  • BCAR3 plays an important role in the signaling pathways of insulin leading to cell cycle progression and cytoskeleton reorganization, but not SLC2A4 translocation
  • RAB5A activity regulates SLC2A4 sorting into insulin-responsive and non-insulin-responsive endosomal compartments: a potential mechanism for development of insulin resistance
  • SIK2 increases SLC2A4 levels, regulates CRTC2, CRTC3, HDAC4 and glucose uptake in adipocytes
  • ZNF407 regulates insulin-stimulated glucose uptake and glucose transporter 4 (SLC2A4) mRNA
  • TCTEX1D2 is a novel STX4 binding protein that functions as a negative regulator of SLC2A4 plasma membrane translocation (pMID: 26200093)
  • TMOD3 is a novel AKT2 effector regulating insulin-stimulated SLC2A4 exocytosis through cortical actin remodeling
  • TBC1D4 (AS160) controls trafficking of the glucose transporter SLC2A4 in adipocytes and skeletal muscle cells
  • MICALL2 is an effector of insulin-activated RAB13, which links to SLC2A4 through ACTN4, localizing SLC2A4 vesicles at the muscle cell periphery to enable their fusion with the membrane
  • transcription factor MEF2A and PLAGL1 mediate MIF-induced SLC2A4 expression through CD74-dependent AMPK activation in cardiomyocytes
  • SLC2A4 traffics predominantly through the specialized RAB10-dependent pathway both before and after insulin stimulation
  • RAB10 is a regulator of insulin-stimulated translocation of the SLC2A4 glucose transporter to the plasma membrane (PM) of adipocytes, which is essential for whole-body glucose homeostasis
  • PID1 serves as an insulin-regulated retention adaptor protein controlling translocation of LRP1 in conjunction with SLC2A4 to the plasma membrane of adipocytes
  • cell & other
    REGULATION
    Other translocated to plasma membrane for insulin stimulated glucose uptake,requiring activation of phosphatidylinositol-3-OH kinase (PI(3)K) and activation of TC10 (essential)
    may be regulated by PLAGL1
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in adipose tissue but preserved in muscle in insuline-resitant states such as obesity and type 2 diabetes
    Susceptibility non insulin dependent diabetes mellitus (type 2)
    Variant & Polymorphism polymorphic variant
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    diabetetype 2 
    promising target for pharmacogenomics of insulin resistance
    cancer  
    therapeutic strategy entailing selective SLC2A4, SLC2A11, SLC2A8 inhibition to specifically target aberrant glucose metabolism in cancer
    ANIMAL & CELL MODELS
    G4A -/- mice