Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

Koumanov, Françoise; Holman, Geoffrey D.

doi:10.1042/bj20070271

Cited by 14 publications

(8 citation statements)

References 14 publications

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“…This pathway involves phosphorylation of TBC1D4 by protein kinase AKT and have led to its alternative designation as AKT substrate of 160 kDa (AS160) (32,33,38,40,44). Experimental suppression of TBC1D4 leads to leaky and insulin-independent release of GLUT4 into the plasma membrane (45).…”

Section: Discussionmentioning

confidence: 99%

“…WNK1 Leads to Increased Expression of GLUT1 at the Cell Surface-In insulin-sensitive adipocytes and skeletal muscle cells TBC1D4 was shown to control the translocation of the insulin-responsive glucose transporter GLUT4 from intracellular storage vesicles to the plasma membrane (33,38). Most other cell types, however, express the transporter GLUT1 for their constitutive uptake of glucose (39).…”

Section: Wnk1 Exists In a Complex With Tbc1d4-mentioning

confidence: 99%

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Protein Kinase WNK1 Promotes Cell Surface Expression of Glucose Transporter GLUT1 by Regulating a Tre-2/USP6-BUB2-Cdc16 Domain Family Member 4 (TBC1D4)-Rab8A Complex

Mendes

Matos

Moniz

et al. 2010

Journal of Biological Chemistry

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One mechanism by which mammalian cells regulate the uptake of glucose is the number of glucose transporter proteins (GLUT) present at the plasma membrane. In insulin-responsive cells types, GLUT4 is released from intracellular stores through inactivation of the Rab GTPase activating protein Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4) (also known as AS160). Here we describe that TBC1D4 forms a protein complex with protein kinase WNK1 in human embryonic kidney (HEK293) cells. We show that WNK1 phosphorylates TBC1D4 in vitro and that the expression levels of WNK1 in these cells regulate surface expression of the constitutive glucose transporter GLUT1. WNK1 was found to increase the binding of TBC1D4 to regulatory 14-3-3 proteins while reducing its interaction with the exocytic small GTPase Rab8A. These effects were dependent on the catalytic activity because expression of a kinase-dead WNK1 mutant had no effect on binding of 14-3-3 and Rab8A, or on surface GLUT1 levels. Together, the data describe a pathway regulating constitutive glucose uptake via GLUT1, the expression level of which is related to several human diseases.WNK1 is one of four human members of the WNK 2 subfamily of serine/threonine protein kinases (1) and is the only family member with a ubiquitous expression pattern (1-4). The WNK1 protein contains 2382 amino acids with a predicted molecular mass of 251 kDa and has its catalytic domain near the N terminus, including the unique sequence variation around catalytically important lysine residues that characterize the WNK subfamily (5, 6). WNK1 contains coiled-coil domains but the bulk sequence reveals no homology to other known protein domains.Currently, the knowledge on WNK1-regulated cellular pathways is still limited (7). On the one hand, WNK1 can affect multiple signaling pathways related to cell proliferation, including the epidermal growth factor-dependent stimulation of ERK5 (8) and the inhibition of Smad2/TGF␤ signaling (9) in HeLa cells. Additionally, insulin-like growth factor 1 treatment of human embryonic kidney (HEK293) cells or adipocytes stimulates protein kinase AKT to phosphorylate WNK1 at threonine residue 60, however, the physiological relevance of this event is unclear because phosphorylation did not affect WNK1 kinase activity, or its subcellular localization (10 -12). On the other hand, WNK1 is involved in restoring osmotic homeostasis. It directly phosphorylates and activates SPAK and OSR1 protein kinases, which interact with and stimulate the activity of the cation chloride co-transporters NKCC1 (13-16) or NCC (14, 17) in HEK293 or HeLa cells. The expression of WNK1 appears also to be part of a pathway involved in inhibitory phosphorylation events of co-transporter KCC (18).Mutations in the WNK1 and WNK4 genes have been linked to pseudo-hypoaldosteronism type II (or Gordon's syndrome), a rare familial form of hypertension (2), which is characterized by increased renal salt reabsorption and decreased potassium secretion. The identified WNK1 mutations increase WNK1 expre...

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Section: Discussionmentioning

confidence: 99%

Section: Wnk1 Exists In a Complex With Tbc1d4-mentioning

confidence: 99%

Protein Kinase WNK1 Promotes Cell Surface Expression of Glucose Transporter GLUT1 by Regulating a Tre-2/USP6-BUB2-Cdc16 Domain Family Member 4 (TBC1D4)-Rab8A Complex

Mendes

Matos

Moniz

et al. 2010

Journal of Biological Chemistry

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“…A number of studies in cultured cells, predominantly 3T3-L1 adipocytes and L6 muscle cells, subsequently established the following model for AS160 function in GLUT4 trafficking (23). Under basal conditions, AS160 localizes to GLUT4 vesicles and is active as a Rab GAP.…”

mentioning

confidence: 98%

Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis

Lansey

Walker

Hargett

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

140

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Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160(-/-)) mice. We observed increased and normal basal glucose uptake in isolated AS160(-/-) adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160(-/-) extensor digitorum longus muscles. In plasma membranes isolated from AS160(-/-) adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160(-/-) adipocytes and normal in AS160(-/-) soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160(-/-) skeletal muscles and liver but not in AS160(-/-) adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis.

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“…Skeletal muscle glucose uptake is accompanied by increased GLUT4 translocation; both insulin and contraction independently stimulate GLUT4 translocation in vivo [10]. One of the main differences between Tbc1d1 and Tbc1d4 is the occurrence of an AMPK (AMP-activated protein kinase) phosphorylation site between the two PTB domains of Tbc1d1 [9]. The PTB domain seems to be relevant for the implication of Tbc1d1 in energy homeostasis, since a non-conservative mutation (R125W) in the PTB domain of Tbc1d1 has recently repeatedly been shown to be associated with severe familial obesity in humans [11,12].…”

mentioning

confidence: 99%

“…In addition, they showed that insulin led to the phosphorylation of Tbc1d1 on a binding site for Akt that is conserved between Tbc1d1 and Tbc1d4. Moreover, Tbc1d1, like Tbc1d4, mediated GLUT4 translocation through an Akt-mediated decrease of Rab GAP activity, indicating that a high level of Rab GAP activity causes suppression of GLUT4 translocation (and thus glucose uptake), whereas a decrease of Rab GAP activity does the opposite [7,9]. In light of this observation, the identified SJL-specific loss-of-function mutation in Tbc1d1 by Chadt et al [1] would thus be expected to contribute to decreased levels of blood glucose through an increased GLUT4 translocation.…”

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confidence: 99%

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Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

Cited by 14 publications

References 14 publications

Protein Kinase WNK1 Promotes Cell Surface Expression of Glucose Transporter GLUT1 by Regulating a Tre-2/USP6-BUB2-Cdc16 Domain Family Member 4 (TBC1D4)-Rab8A Complex

Protein Kinase WNK1 Promotes Cell Surface Expression of Glucose Transporter GLUT1 by Regulating a Tre-2/USP6-BUB2-Cdc16 Domain Family Member 4 (TBC1D4)-Rab8A Complex

Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis

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