Clathrin-mediated Endocytosis of Na+,K+-ATPase in Response to Parathyroid Hormone Requires ERK-dependent Phosphorylation of Ser-11 within the α1-Subunit

Khundmiri, Syed Jalal; Bertorello, Alejandro M.; Delamere, Nicholas A.; Lederer, Eleanor

doi:10.1074/jbc.m311715200

Cited by 66 publications

(58 citation statements)

References 25 publications

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“…It involves lysosomal breakdown of Na/Pi-II proteins as a result of activation of several protein kinases (PK) (5). These include PKA, PKC, and PKG and the ERK/MAPK pathway (4,21,43,44). The NHERF-1 interacts directly with the Na/Pi-4 transporter and is involved in the signaling pathway of PTH inhibition of P uptake by OK cells (21).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A␤ gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1␣-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.Phosphate (Pi) homeostasis is essential to life and is dependent on active renal reabsorption. In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2). The kidney has an intrinsic P sensing system that regulates the activity of apical brush border membrane type II Na/Pi co-transporters (3). However, it is still not known how the organism senses changes in serum P.There are three mammalian Na/Pi co-transporter families: types I through III. Type II Na/Pi activity is responsible for Ͼ80% of renal P reabsorption and contains three isoforms-IIa through c-of which IIa is the major factor in renal P reabsorption and regulation in adult mice (4). Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11). In the rat, a cis acting element in the type II Na/Pi co-transporter (Na/Pi-2) mRNA at the junction of the coding region and the 3'-untranslated region (UTR) interacts with trans acting renal cytosolic proteins and determines Na/Pi-2 mRNA stability in response to dietary P restriction (12). An additional level of regulation of Na/Pi-2 is its translational control by a low-P diet (10).The renal type II Na/Pi co-transporte...

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Section: Discussionmentioning

confidence: 99%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

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“…For example, the Na,K-ATPase activity could either be stimulated or inhibited by ERK1/2-dependent phosphorylation of the ␣ 1 subunit (4,35). Long term stimulation of ERK1/2 has been shown to inhibit transcription of ENaC subunits in mouse collecting duct cells (mCT1) and in salivary epithelial cells (36 -38).…”

Section: Erk1/2 Controls Nak-atpase Activity In the Principal Cellmentioning

confidence: 99%

“…In the kidney, the ERK1/2 pathway is involved in the hormonal regulation of different apical and basolateral channels or transporters expressed along the nephron for maintaining the extracellular fluid homeostasis. In the proximal tubule the ERK1/2 pathway is involved in the internalization of the Na ϩ /phosphate co-transporter at the apical membrane and in the activation of Na,K-ATPase at the basolateral membrane (3,4). In the thick ascending limb the ERK1/2 pathway is also involved in the inhibition of basolateral Na ϩ /H ϩ exchange activity and HCO 3 Ϫ absorption by nerve growth factor (5).…”

mentioning

confidence: 99%

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Michlig

Mercier

Doucet

et al. 2004

Journal of Biological Chemistry

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The collecting duct of normal kidney exhibits significant activity of the MEK1/2-ERK1/2 pathway as shown in vivo by immunostaining of phosphorylated active ERK1/2 (pERK1/2). The MEK1/2-ERK1/2 pathway controls many different ion transports both in proximal and distal nephron, raising the question of whether this pathway is involved in the basal and/or hormone-dependent transepithelial sodium reabsorption in the principal cell of the cortical collecting duct (CCD), a process mediated by the apical epithelial sodium channel and the basolateral sodium pump (Na,K-ATPase). To answer this question we used ex vivo microdissected CCDs from normal mouse kidney or in vitro cultured mpkCCD cl4 principal cells. Significant basal levels of pERK1/2 were observed ex vivo and in vitro. Aldosterone and vasopressin, known to up-regulate sodium reabsorption in CCDs, did not change ERK1/2 activity either ex vivo or in vitro. Basal and aldosterone-or vasopressin-stimulated sodium transport was down-regulated by the MEK1/2 inhibitor PD98059, in parallel with a decrease in pERK1/2 in vitro. The activity of Na,K-ATPase but not that of epithelial sodium channel was inhibited by MEK1/2 inhibitors in both unstimulated and aldosterone-or vasopressin-stimulated CCDs in vitro. Cell surface biotinylation showed that intrinsic activity rather than cell surface expression of Na,K-ATPase was controlled by pERK1/2. PD98059 also significantly inhibited the activity of Na,K-ATPase ex vivo. Our data demonstrate that the ERK1/2 pathway controls Na,K-ATPase activity and transepithelial sodium transport in the principal cell and indicate that basal constitutive activity of the ERK1/2 pathway is a critical component of this control.The extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) 1 pathway, also known as p42 and p44 mitogen-activated protein (MAP) kinase pathway, plays a critical role in cellular responses to a wide variety of external stimuli including hormones, growth factors, and environmental stress (for review, see Refs. 1 and 2). The ERK1/2 pathway is a three-step kinase cascade in which ERK1/2 kinases are phosphorylated/ activated by two immediate upstream MAP kinases (MEK1 and MEK2 (MEK1/2)) that are in turn phosphorylated/activated by several MAP kinases (i.e. MOS, C-Raf, and B-Raf). Activated ERK1/2 (pERK1/2) phosphorylates various downstream effectors involved in differentiation, proliferation, apoptosis, survival, cellular metabolism, and ion transport. The MAP kinase cascade may also be constitutively activated independent of external stimuli or ligands. This basal activity is the result of the balance between positive and negative factors regulating MAP kinases activity; that is, phosphatases, subcellular localization, expression of scaffold proteins, and activity of other kinases. In the kidney, the ERK1/2 pathway is involved in the hormonal regulation of different apical and basolateral channels or transporters expressed along the nephron for maintaining the extracellular fluid homeostasis. In the proximal tubule the ERK...

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“…PI3K has been shown to be necessary for the internalization of several growth factor receptors as it controls initial stages of the coated pit assembly (54 -58). Several studies suggest that ERK is not directly involved in the regulation of the clathrin-dependent endocytosis machinery; for the Na,K-ATPase, however, it has been shown that ERK-mediated phosphorylation of the cytoplasmic domain is required for its endocytosis (59).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitination and Endocytosis of Cell Adhesion Molecule DM-GRASP Regulate Its Cell Surface Presence and Affect Its Role for Axon Navigation

Thelen

Georg

Bertuch

et al. 2008

Journal of Biological Chemistry

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DM-GRASP, cell adhesion molecule of the immunoglobulin superfamily, has been shown to promote growth and navigation of axons. We here demonstrate that clustering of DM-GRASP in the plasma membrane induces its rapid internalization via dynamin-and clathrin-dependent endocytosis, which is controlled by phosphatidylinositol 3-kinase and mitogen-activated protein kinase ERK. The clustering of DM-GRASP activates ERK; the intensity and duration of ERK activation by DM-GRASP do not depend on rapid clathrin-mediated internalization of DM-GRASP. Moreover, the preference of retinal ganglion cell axons for DM-GRASP-coated micro-lanes requires clathrin-mediated endocytosis for the appropriate axonal turning reactions at substrate borders. Because the intracellular domain of DM-GRASP does not contain motifs for direct interactions with the endocytosis machinery, we performed a yeast two-hybrid screen to identify intracellular proteins mediating the uptake of DM-GRASP and isolated ubiquitin. Immunoprecipitation of DM-GRASP coexpressed with ubiquitin revealed that one or two ubiquitin(s) are attached to the intracellular domain of cell surface-resident DM-GRASP. Furthermore, elevated ubiquitination levels result in a decrease of cell surface-resident DM-GRASP as well as in the amount of total DM-GRASP. The endocytosis rate is not affected, but the delivery to multivesicular bodies is increased, indicating that DM-GRASP ubiquitination enhances its sorting into the degradation pathway. Together, our data show that ubiquitination and endocytosis of DM-GRASP in concert regulate its cell surface concentration, which is crucial for its function in axon navigation.

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Clathrin-mediated Endocytosis of Na+,K+-ATPase in Response to Parathyroid Hormone Requires ERK-dependent Phosphorylation of Ser-11 within the α1-Subunit

Abstract: Parathyroid hormone (PTH) inhibits Na

Cited by 66 publications

References 25 publications

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

ERK1/2 Controls Na,K-ATPase Activity and Transepithelial Sodium Transport in the Principal Cell of the Cortical Collecting Duct of the Mouse Kidney

Ubiquitination and Endocytosis of Cell Adhesion Molecule DM-GRASP Regulate Its Cell Surface Presence and Affect Its Role for Axon Navigation

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