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10.1073/pnas.1418342111 http://scihub22266oqcxt.onion/10.1073/pnas.1418342111 25313067!4217463!25313067     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Proc+Natl+Acad+Sci+U+S+A 2014 ; 111 (43): 15556-61 Nephropedia Template TP {{tp|p=25313067|t=2014. Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation |pdf=|usr=}}{{25313067}} gab.com Text Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=25313067 #FOAvip Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K(+) reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K(+) secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)--components of an E3 ubiquitin ligase complex that targets WNKs for degradation--cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3(S433) phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K(+) secretion in the setting of volume depletion. Twit Text FOAVip Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=25313067 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25313067 #FOAvip English Wikipedia <ref>{{Cite pmid|25313067}}</ref> Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation #MMPMID25313067 Shibata S; Arroyo JP; Castaneda-Bueno M; Puthumana J; Zhang J; Uchida S; Stone KL; Lam TT; Lifton RP Proc Natl Acad Sci U S A 2014[Oct]; 111 (43): 15556-61 PMID25313067show ga Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K(+) reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K(+) secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)--components of an E3 ubiquitin ligase complex that targets WNKs for degradation--cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3(S433) phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K(+) secretion in the setting of volume depletion. |*Proteolysis[MESH] |*Signal Transduction[MESH] |Adaptor Proteins, Signal Transducing[MESH] |Amino Acid Sequence[MESH] |Angiotensin II/*metabolism[MESH] |Animals[MESH] |Carrier Proteins/chemistry/*metabolism[MESH] |Cell Line[MESH] |Humans[MESH] |Kidney/metabolism[MESH] |Mice, Inbred C57BL[MESH] |Microfilament Proteins[MESH] |Molecular Sequence Data[MESH] |Phosphorylation[MESH] |Phosphoserine/metabolism[MESH] |Protein Binding[MESH] |Protein Kinase C/*metabolism[MESH]Angiotensin II signaling via protein kinase C phosphorylates Kelch-lik(epmc).pdf DeepDyve Pubget Overpricing