Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking

Zhou, Zhou; Menzel, Franziska; Benninghoff, Tim; Chadt, Alexandra; Du, Chen; Holman, Geoffrey D.; Al-Hasani, Hadi

doi:10.1002/1873-3468.12509

Cited by 17 publications

(24 citation statements)

References 37 publications

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“…measurements of GTP hydrolysis rates of recombinant GSTtagged Rab GTPases in the absence and presence of the intact GAP domain resulted in identification of several Rabs that are considered to be substrates, including Rab8a, Rab10, Rab14, and Rab28 (26). Similar results were reported for the truncated GAP domain of the related TBC1D4 (13).…”

Section: Regulation Of Recombinant Tbc1d1 In Vitrosupporting

confidence: 62%

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AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP

Mafakheri

Flörke

Kanngießer

et al. 2018

Journal of Biological Chemistry

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In skeletal muscle, the Rab GTPase-activating (GAP) protein TBC1D1 is phosphorylated by AKT and AMP-activated protein kinase (AMPK) in response to insulin and muscle contraction. Genetic ablation of Tbc1d1 or mutation of distinct phosphorylation sites impairs intracellular GLUT4 retention and GLUT4 traffic, presumably through alterations of the activation state of downstream Rab GTPases. Previous studies have focused on characterizing the C-terminal GAP domain of TBC1D1 that lacks the known phosphorylation sites, as well as putative regulatory domains. As a result, it has been unclear how phosphorylation of TBC1D1 would regulate its activity. In the present study, we have expressed, purified, and characterized recombinant full-length TBC1D1 in Sf9 insect cells via the baculovirus system. Full-length TBC1D1 showed RabGAP activity toward GLUT4-associated Rab8a, Rab10, and Rab14, indicating similar substrate specificity as the truncated GAP domain. However, the catalytic activity of the full-length TBC1D1 was markedly higher than that of the GAP domain. Although in vitro phosphorylation of TBC1D1 by AKT or AMPK increased 14-3-3 binding, it did not alter the intrinsic RabGAP activity. However, we found that TBC1D1 interacts through its N-terminal PTB domains with the cytoplasmic domain of the insulin-regulated aminopeptidase, a resident protein of GLUT4 storage vesicles, and this binding is disrupted by phosphorylation of TBC1D1 by AKT or AMPK. In summary, our findings suggest that other regions outside the GAP domain may contribute to the catalytic activity of TBC1D1. Moreover, our data indicate that recruitment of TBC1D1 to GLUT4-containing vesicles and not its GAP activity is regulated by insulin and contraction-mediated phosphorylation.

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Section: Regulation Of Recombinant Tbc1d1 In Vitrosupporting

confidence: 62%

“…S1). We and others have shown previously that both Rab8a and Rab14 are substrates for the truncated GAP domain of TBC1D1 in vitro (9,26). We therefore compared the GAP activities toward the different GTP-loaded Rabs.…”

Section: Regulation Of Recombinant Tbc1d1 In Vitromentioning

confidence: 99%

AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP

Mafakheri

Flörke

Kanngießer

et al. 2018

Journal of Biological Chemistry

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“…Consistent with the fiber-type-specific RabGAP expression pattern, stimulation of glucose transport is impaired mainly in glycolytic skeletal muscle of Tbc1d1-deficient mice, whereas Tbc1d4-knockout mice display defective glucose uptake after stimulation in oxidative skeletal muscle , Chadt et al 2015. Moreover, insulinstimulated glucose transport is also substantially reduced in adipocytes from Tbc1d4-deficient mice (Chadt et al 2015, Zhou et al 2017. While the expected increase in basal glucose transport due to RabGAP depletion is shown for cultured 3T3-L1 adipocytes (Roach et al 2007), this finding is not consistently validated in intact skeletal muscles or primary adipocytes (Chadt et al 2015).…”

Section: Rabgap Deficiency Leads To Reduced Glut4 Protein Abundance Isupporting

confidence: 59%

RabGAPs in skeletal muscle function and exercise

Espelage

Al-Hasani

Chadt

2020

Journal of Molecular Endocrinology

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The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.

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“…RAB28 has been suggested to participate in lysosomal delivery of endocytosed surface protein in unicellular trypanosomes (31), angiotensin-induced NF-B nuclear delivery and activation in rat endothelia (32), glucose transporter 4 plasma membrane trafficking in mouse skeletal muscle (33), and intraflagellar transport in Caenorhabditis elegans (34).…”

Section: Discussionmentioning

confidence: 99%

The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium

Ying

Boldt

Ueffing

et al. 2018

Journal of Biological Chemistry

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RAB28, a member of the RAS oncogene family, is a ubiquitous, farnesylated, small GTPase of unknown function present in photoreceptors and the retinal pigmented epithelium (RPE). Nonsense mutations of the human gene cause recessive cone-rod dystrophy 18 (CRD18), characterized by macular hyperpigmentation, progressive loss of visual acuity, RPE atrophy, and severely attenuated cone and rod electroretinography (ERG) responses. In an attempt to elucidate the disease-causing mechanism, we generated mice by deleting exon 3 and truncating RAB28 after exon 2. We found that mice recapitulate features of the human dystrophy ( they exhibited reduced cone and rod ERG responses and progressive retina degeneration). Cones of mice extended their outer segments (OSs) to the RPE apical processes and formed enlarged, balloon-like distal tips before undergoing degeneration. The visual pigment content of WT and cones was comparable before the onset of degeneration. Cone phagosomes were almost absent in mice, whereas rod phagosomes displayed normal levels. A protein-protein interaction screen identified several RAB28-interacting proteins, including the prenyl-binding protein phosphodiesterase 6 δ-subunit (PDE6D) and voltage-gated potassium channel subfamily J member 13 (KCNJ13) present in the RPE apical processes. Of note, the loss of PDE6D prevented delivery of RAB28 to OSs. Taken together, these findings reveal that RAB28 is required for shedding and phagocytosis of cone OS discs.

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Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking

Cited by 17 publications

References 37 publications

AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP

AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP

RabGAPs in skeletal muscle function and exercise

The small GTPase RAB28 is required for phagocytosis of cone outer segments by the murine retinal pigmented epithelium

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