Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin

Bouley, Richard; Nunes, Paula; Andriopoulos, Billy; McLaughlin, Margaret; Webber, Matthew J.; Lin, Herbert Y.; Babitt, Jodie L.; Gardella, Thomas J.; Ausiello, Dennis A.; Brown, Dennis

doi:10.1152/ajprenal.00438.2011

Cited by 4 publications

(3 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20,21 A similar pattern was observed with AG-490, a combined JAK-2 and EGFR inhibitor. The role of the JAK/STAT signaling pathway was ruled out, because TG-101348, a selective JAK-2 inhibitor, did not induce AQP2 membrane accumulation.…”

Section: Egfr Inhibitors Induce Membranesupporting

confidence: 62%

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

Self Cite

View full text Add to dashboard Cite

Nephrogenic diabetes insipidus (NDI) is caused by impairment of vasopressin (VP) receptor type 2 signaling. Because potential therapies for NDI that target the canonical VP/cAMP/protein kinase A pathway have so far proven ineffective, alternative strategies for modulating aquaporin 2 (AQP2) trafficking have been sought. Successful identification of compounds by our high-throughput chemical screening assay prompted us to determine whether EGF receptor (EGFR) inhibitors stimulate AQP2 trafficking and reduce urine output. Erlotinib, a selective EGFR inhibitor, enhanced AQP2 apical membrane expression in collecting duct principal cells and reduced urine volume by 45% after 5 days of treatment in mice with lithiuminduced NDI. Similar to VP, erlotinib increased exocytosis and decreased endocytosis in LLC-PK1 cells, resulting in a significant increase in AQP2 membrane accumulation. Erlotinib increased phosphorylation of AQP2 at Ser-256 and Ser-269 and decreased phosphorylation at Ser-261 in a dose-dependent manner. However, unlike VP, the effect of erlotinib was independent of cAMP, cGMP, and protein kinase A. Conversely, EGF reduced VP-induced AQP2 Ser-256 phosphorylation, suggesting crosstalk between VP and EGF in AQP2 trafficking and a role of EGF in water homeostasis. These results reveal a novel pathway that contributes to the regulation of AQP2-mediated water reabsorption and suggest new potential therapeutic strategies for NDI treatment.

show abstract

Section: Egfr Inhibitors Induce Membranesupporting

confidence: 62%

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

Self Cite

View full text Add to dashboard Cite

show abstract

“…We then used our GFP-tagged V2R cell model. At baseline, V2R accumulates in the plasma membrane, and, with VP treatment, we observed a marked internalization of V2R-GFP, as previously described (50,67). This suggests that the clathrin-mediated endocytosis process that is necessary for receptor downregulation after ligand binding still occurs when Arp2/3 activity is inhibited (Fig.…”

Section: Arp2/3 Inhibition Does Not Affect the Endocytotic Pathwaysupporting

confidence: 85%

Actin-related protein 2/3 complex plays a critical role in the aquaporin-2 exocytotic pathway

Liu

Cheung

Dinesh

et al. 2021

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

The trafficking of proteins such as aquaporin-2 (AQP2) in the exocytotic pathway requires an active actin cytoskeleton network, but the mechanism is incompletely understood. Here, we show that the actin-related protein (Arp) 2/3 complex, a key factor in actin filament branching and polymerization, is involved in the shuttling of aquaporin-2 (AQP2) between the trans Golgi network (TGN) and the plasma membrane. Arp2/3 inhibition (using CK-666) or siRNA knockdown blocks vasopressin induced AQP2 membrane accumulation, and induces the formation of distinct AQP2 perinuclear patches positive for markers of TGN-derived clathrin coated vesicles. After a 20oC cold block, AQP2 formed perinuclear patches due continuous endocytosis coupled with inhibition of exit from the TGN-associated vesicles. Upon rewarming, AQP2 normally leaves the TGN, and redistributes into the cytoplasm, entering the exocytotic pathway. Inhibition of Arp2/3 blocked this process, and trapped AQP2 in clathrin positive vesicles. Taken together, these results suggest that Arp2/3 is essential for AQP2 trafficking, specifically for its delivery into the post-TGN exocytotic pathway to the plasma membrane.

show abstract

“…We then tested whether overexpression of XLαs affects internalization of the type 2 vasopressin receptor (V2R), another GPCR that internalizes via clathrin-mediated endocytosis (45,46). HEK293T cells were cotransfected with XLαs-GFP and V2R cDNA and treated with tetramethylrhodamine-labeled vasopressin (VP-TMR) for 5 min.…”

Section: Overexpression Of Xlαs Inhibits G Protein-coupled Receptormentioning

confidence: 99%

Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo

Bouley

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Alterations in the activity/levels of the extralarge G protein α-subunit (XLαs) are implicated in various human disorders, such as perinatal growth retardation. Encoded by , XLαs is partly identical to the α-subunit of the stimulatory G protein (Gsα), but the cellular actions of XLαs remain poorly defined. Following an initial proteomic screen, we identified sorting nexin-9 (SNX9) and dynamins, key components of clathrin-mediated endocytosis, as binding partners of XLαs. Overexpression of XLαs in HEK293 cells inhibited internalization of transferrin, a process that depends on clathrin-mediated endocytosis, while its ablation by CRISPR/Cas9 in an osteocyte-like cell line (Ocy454) enhanced it. Similarly, primary cardiomyocytes derived from XLαs knockout (XLKO) pups showed enhanced transferrin internalization. Early postnatal XLKO mice showed a significantly higher degree of cardiac iron uptake than wild-type littermates following iron dextran injection. In XLKO neonates, iron and ferritin levels were elevated in heart and skeletal muscle, where XLαs is normally expressed abundantly. XLKO heart and skeletal muscle, as well as XLKO Ocy454 cells, showed elevated SNX9 protein levels, and siRNA-mediated knockdown of SNX9 in XLKO Ocy454 cells prevented enhanced transferrin internalization. In transfected cells, XLαs also inhibited internalization of the parathyroid hormone and type 2 vasopressin receptors. Internalization of transferrin and these G protein-coupled receptors was also inhibited in cells expressing an XLαs mutant missing the Gα portion, but not Gsα or an N-terminally truncated XLαs mutant unable to interact with SNX9 or dynamin. Thus, XLαs restricts clathrin-mediated endocytosis and plays a critical role in iron/transferrin uptake in vivo.

show abstract

Heterologous downregulation of vasopressin type 2 receptor is induced by transferrin

Cited by 4 publications

References 71 publications

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Actin-related protein 2/3 complex plays a critical role in the aquaporin-2 exocytotic pathway

Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo

Contact Info

Product

Resources

About