An essential role for the Glut1 PDZ-binding motif in growth factor regulation of Glut1 degradation and trafficking

Wieman, Heather L.; Horn, Sarah R.; Jacobs, Sarah R.; Altman, Brian J.; Kornbluth, Sally; Rathmell, Jeffrey C.

doi:10.1042/bj20081422

Cited by 47 publications

(67 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At steady state, GLUT1 is localized at the plasma membrane from where it undergoes continuous rounds of endocytosis and PDZ ligand-dependent endosome-to-plasma membrane recycling [9], the latter being mediated by the SNX27-retromer [8]. In the absence of retromer, GLUT1 accumulates in the lysosome and is degraded [8].…”

Section: Resultsmentioning

confidence: 99%

Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation

et al. 2014

View full text Add to dashboard Cite

SummaryRetromer is a protein assembly that plays a central role in orchestrating export of transmembrane-spanning cargo proteins from endosomes into retrieval pathways destined for the Golgi apparatus and the plasma membrane [1]. Recently, a specific mutation in the retromer component VPS35, VPS35(D620N), has linked retromer dysfunction to familial autosomal dominant and sporadic Parkinson disease [2, 3]. However, the effect of this mutation on retromer function remains poorly characterized. Here we established that in cells expressing VPS35(D620N) there is a perturbation in endosome-to-TGN transport but not endosome-to-plasma membrane recycling, which we confirm in patient cells harboring the VPS35(D620N) mutation. Through comparative stable isotope labeling by amino acids in cell culture (SILAC)-based analysis of wild-type VPS35 versus the VPS35(D620N) mutant interactomes, we establish that the major defect of the D620N mutation lies in the association to the actin-nucleating Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex. Moreover, using isothermal calorimetry, we establish that the primary defect of the VPS35(D620N) mutant is a 2.2 ± 0.5-fold decrease in affinity for the WASH complex component FAM21. These data define the primary molecular defect in retromer assembly that arises from the VPS35(D620N) mutation and, by revealing functional effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in Parkinson disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation

et al. 2014

View full text Add to dashboard Cite

show abstract

“…We have shown that the 38-residue cytosolic tail of Glut1 is necessary for this localization pattern. The last four amino acids (DSQV) constitute a PDZ-binding motif that is necessary for an interaction with the protein GIPC (Bunn et al, 1999), which has been shown to regulate recycling of internalized Glut1 to the plasma membrane in hematopoietic cells (Wieman et al, 2009). Two other proteins, the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 (Giorgino et al, 2000) and the lipid raft protein stomatin (Zhang et al, 2001;Zhang et al, 1999), have also been reported to associate with the cytosolic tail of Glut1.…”

Section: Fig 3 Immunogold Analysis Of Glut1 In Xenopus Retina Sectimentioning

confidence: 99%

“…Previous work in our laboratory has demonstrated that the membrane-rich outer segment is a preferred destination for membrane proteins heterologously expressed in tadpole rods and that exclusion of these proteins from the outer segment requires the presence of intrinsic targeting information to specify localization elsewhere in the cell (Baker et al, 2008). Because the cytosolic Cterminal tail of Glut1 has been implicated in the regulation of its intracellular trafficking in other cell types (Verhey et al, 1993;Wieman et al, 2009), we generated transgenic tadpoles expressing a truncated Glut1 construct (GFP-Glut138) lacking the entire C terminus. Strikingly, although this truncation did not prevent the protein from reaching the synaptic terminal and inner segment plasma membrane, it did allow the construct to gain entry into the rod outer segment, including the disc membranes (Fig.…”

Section: Active Exclusion Of Glut1 From Rod Outer Segments Of Transgementioning

confidence: 99%

Facilitative glucose transporter Glut1 is actively excluded from rod outer segments

Gospe

Baker

Arshavsky

2010

Journal of Cell Science

View full text Add to dashboard Cite

SummaryPhotoreceptors are among the most metabolically active cells in the body, relying on both oxidative phosphorylation and glycolysis to satisfy their high energy needs. Local glycolysis is thought to be particularly crucial in supporting the function of the photoreceptor's light-sensitive outer segment compartment, which is devoid of mitochondria. Accordingly, it has been commonly accepted that the facilitative glucose transporter Glut1 responsible for glucose entry into photoreceptors is localized in part to the outer segment plasma membrane. However, we now demonstrate that Glut1 is entirely absent from the rod outer segment and is actively excluded from this compartment by targeting information present in its cytosolic C-terminal tail. Our data indicate that glucose metabolized in the outer segment must first enter through other parts of the photoreceptor cell. Consequently, the entire energy supply of the outer segment is dependent on diffusion of energy-rich substrates through the thin connecting cilium that links this compartment to the rest of the cell.

show abstract

“…Localization of GLUT1 to the cell surface is largely regulated through its endocytic traffic (5)(6)(7)(8)(9)(10)(11), controlled, in non-transformed cells, by cytokine stimulation (12,13) or energy stress (6). In cancer cells, several oncogenic lesions, including hyper activation of the EGFR/PI3K/AKT signaling pathway, induce accumulation of GLUT1 at the cell surface resulting in increased aerobic glycolysis (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis

et al. 2018

View full text Add to dashboard Cite

USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation. Significance: USP6NL overexpression leads to glycolysis addiction of breast cancer cells and presents a point of metabolic vulnerability for therapeutic targeting in a subset of aggressive basal-like breast tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3432/F1.large.jpg. Cancer Res; 78(13); 3432–44. ©2018 AACR.

show abstract

An essential role for the Glut1 PDZ-binding motif in growth factor regulation of Glut1 degradation and trafficking

Abstract: Cell surface localization of the glucose transporter, Glut1, is a cytokine-controlled process essential to support the metabolism and survival of hematopoietic cells. Molecular mechanisms that regulate Glut1 trafficking, however, are not certain. Here we show a C-terminal PDZ

Cited by 47 publications

References 41 publications

Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation

Retromer Binding to FAM21 and the WASH Complex Is Perturbed by the Parkinson Disease-Linked VPS35(D620N) Mutation

Facilitative glucose transporter Glut1 is actively excluded from rod outer segments

High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis

Contact Info

Product

Resources

About