MAL/VIP17, a New Player in the Regulation of NKCC2 in the Kidney

Carmosino, Monica; Rizzo, Federica; Procino, Giuseppe; Basco, Davide; Valenti, Giovanna; Forbush, Bliss; Schaeren‐Wiemers, Nicole; Caplan, Michael J.; Svelto, María

doi:10.1091/mbc.e10-05-0456

Cited by 33 publications

(26 citation statements)

References 42 publications

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“…In polarized epithelial cells, MAL mediates direct vesicular transport of cargo to the apical surface (17,18) and stabilization of specific proteins at the apical membrane (46,47). Our present results indicate that, in polarized T cells, MAL regulates membrane order at the IS and uses both direct vesicular transport and plasma membrane retention mechanisms to ensure correct sorting of Lck and LAT to the cSMAC.…”

Section: Discussionmentioning

confidence: 57%

“…This observation indicates that LAT targeting to the cSMAC occurs once it has arrived at the IS by selective retention into MAL-enriched membranes. This retention might be reminiscent of the MAL-dependent stabilization of specific apical proteins described in polarized epithelial cells (46,47). Unlike LAT, Lck was transported in MAL-positive vesicles from pericentriolar endosomes to the place where MAL accumulates, regardless of whether it was the cSMAC or the pSMAC.…”

Section: Discussionmentioning

confidence: 70%

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MAL Protein Controls Protein Sorting at the Supramolecular Activation Cluster of Human T Lymphocytes

Antón

Andrés-Delgado

Reglero-Real

et al. 2011

The Journal of Immunology

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T cell membrane receptors and signaling molecules assemble at the immunological synapse (IS) in a supramolecular activation cluster (SMAC), organized into two differentiated subdomains: the central SMAC (cSMAC), with the TCR, Lck, and linker for activation of T cells (LAT), and the peripheral SMAC (pSMAC), with adhesion molecules. The mechanism of protein sorting to the SMAC subdomains is still unknown. MAL forms part of the machinery for protein targeting to the plasma membrane by specialized mechanisms involving condensed membranes or rafts. In this article, we report our investigation of the dynamics of MAL during the formation of the IS and its role in SMAC assembly in the Jurkat T cell line and human primary T cells. We observed that under normal conditions, a pool of MAL rapidly accumulates at the cSMAC, where it colocalized with condensed membranes, as visualized with the membrane fluorescent probe Laurdan. Mislocalization of MAL to the pSMAC greatly reduced membrane condensation at the cSMAC and redistributed machinery involved in docking microtubules or transport vesicles from the cSMAC to the pSMAC. As a consequence of these alterations, the raft-associated molecules Lck and LAT, but not the TCR, were missorted to the pSMAC. MAL, therefore, regulates membrane order and the distribution of microtubule and transport vesicle docking machinery at the IS and, by doing so, ensures correct protein sorting of Lck and LAT to the cSMAC.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 70%

MAL Protein Controls Protein Sorting at the Supramolecular Activation Cluster of Human T Lymphocytes

Antón

Andrés-Delgado

Reglero-Real

et al. 2011

The Journal of Immunology

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“…It is extremely unlikely that the increased activation that we are seeing is not due to NKCC2 activation, which is more abundantly expressed in kidney and the TAL specifically, the same site in which renal Casr is heavily expressed and targeted by our experiments. On the basis of the validity of the R5 antibody to examine NKCC2 expression 23 and the experimental model that we used in our study, we are confident that our data indicated NKCC2 activation. QPCR studies on the TAL genes KCNJ1 (renal outer medullary potassium channel, ROMK) and CLCNKB (voltage-gated basolateral chloride channel) showed no difference in relative expression (Supplemental Figure 2, ) transport by interaction with the heteromeric Claudin16/19 complex in the TAL.…”

Section: Effects Of Renal Casr Deficiency On the Talmentioning

confidence: 57%

Deficiency of the Calcium-Sensing Receptor in the Kidney Causes Parathyroid Hormone–Independent Hypocalciuria

Toka

Al-Romaih

Koshy

et al. 2012

Journal of the American Society of Nephrology

130

112

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Rare loss-of-function mutations in the calcium-sensing receptor (Casr) gene lead to decreased urinary calcium excretion in the context of parathyroid hormone (PTH)-dependent hypercalcemia, but the role of Casr in the kidney is unknown. Using animals expressing Cre recombinase driven by the Six2 promoter, we generated mice that appeared grossly normal but had undetectable levels of Casr mRNA and protein in the kidney. Baseline serum calcium, phosphorus, magnesium, and PTH levels were similar to control mice. When challenged with dietary calcium supplementation, however, these mice had significantly lower urinary calcium excretion than controls (urinary calcium to creatinine, 0.3160.03 versus 0.6360.14; P=0.001). Western blot analysis on whole-kidney lysates suggested an approximately four-fold increase in activated Na + -K + -2Cl 2 cotransporter (NKCC2). In addition, experimental animals exhibited significant downregulation of Claudin14, a negative regulator of paracellular cation permeability in the thick ascending limb, and small but significant upregulation of Claudin16, a positive regulator of paracellular cation permeability. Taken together, these data suggest that renal Casr regulates calcium reabsorption in the thick ascending limb, independent of any change in PTH, by increasing the lumen-positive driving force for paracellular Ca 2+ transport.

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“…Thus it will be important for future studies to determine whether this occurs in the kidney and whether heterodimer formation is favored in the DCT, perhaps as a consequence of an optimal abundance of OSR1 and full-length SPAK. It is also possible that Cab39/MO25␣ or other scaffolding proteins (35,36) stabilize SPAK and OSR1 differently in the TAL and DCT. Our new observation that Cab39/MO25␣ colocalizes with SPAK and OSR1 specifically in the renal DCT and TAL suggests that Cab39/MO25␣ participates in a functionally important complex with SPAK and OSR1 in both nephron segments as it does with LKB1 and the pseudokinase STRAD in other cells (37).…”

Section: Discussionmentioning

confidence: 99%

SPAK Isoforms and OSR1 Regulate Sodium-Chloride Co-transporters in a Nephron-specific Manner

Grimm

Taneja

Liu

et al. 2012

Journal of Biological Chemistry

123

159

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Background: Full-length SPAK is thought to be necessary and sufficient to activate NCC in the distal convoluted tubule (DCT). Results: SPAK knock-out disrupts a signaling network, involving OSR1, in the DCT but not the TAL, preventing NCC activation. Conclusion: SPAK and OSR1 function interdependently in the DCT to positively regulate NCC. Significance: This study provides insights into the mechanisms whereby SPAK/OSR1 regulates renal salt transport.

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MAL/VIP17, a New Player in the Regulation of NKCC2 in the Kidney

Cited by 33 publications

References 42 publications

MAL Protein Controls Protein Sorting at the Supramolecular Activation Cluster of Human T Lymphocytes

MAL Protein Controls Protein Sorting at the Supramolecular Activation Cluster of Human T Lymphocytes

Deficiency of the Calcium-Sensing Receptor in the Kidney Causes Parathyroid Hormone–Independent Hypocalciuria

SPAK Isoforms and OSR1 Regulate Sodium-Chloride Co-transporters in a Nephron-specific Manner

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