Regulation of SR-BI protein levels by phosphorylation of its associated protein, PDZK1

Nakamura, Toshiyuki; Shibata, Norihito; Nishimoto-Shibata, Takako; Feng, Dongdong; Ikemoto, Mamoru; Motojima, Kiyoto; Iso-O, Naoyuki; Tsukamoto, Kazuhisa; Tsujimoto, Masafumi; Arai, Hiroyuki

doi:10.1073/pnas.0506679102

Cited by 47 publications

(51 citation statements)

References 36 publications

(47 reference statements)

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“…endocrine) seem to influence the relationship of NHERF proteins with their substrates. Phosphorylation of NHERF3 at Ser 509 by PKA and glucagon was associated with increased expression of the scavenger receptor class B type I and PDZK1, which resulted in decreased plasma high density lipoprotein levels (50). Although the details responsible for NHERF3-dependent regulation of NHE3 activity remain to be determined, the results of the current study appear to represent another example of the highly regulated association of the NHERFs with their ligands.…”

Section: Discussionmentioning

confidence: 79%

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

Zachos¹,

Li²,

Kovbasnjuk³

et al. 2009

Journal of Biological Chemistry

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Elevated intracellularIn normal digestive physiology, the brush border (BB) 2 Na ϩ /H ϩ exchanger, NHE3, mediates the majority of the NaCl and NaHCO 3 absorption in the ileum (1). Sequential inhibition and stimulation of NHE3 occur as part of digestive physiology. Short-term regulation of NHE3 activity is achieved through a variety of factors that affect NHE3 turnover number and/or surface expression and often involve a role for the cytoskeleton and accessory proteins, including the multi-PDZ domain containing proteins, NHERF1 and NHERF2 (1, 2). However, many details of this regulation are not understood.The NHERF (Na ϩ /H ϩ exchanger regulatory factor) family of multi-PDZ domain containing proteins consists of four evolutionarily related members, all of which are expressed in epithelial cells of the mammalian small intestine (2). NHERF1 and NHERF2 have been previously shown to contribute to acute NHE3 stimulation and inhibition (3-10). Recently, two additional PDZ domain containing proteins, termed NHERF3/ PDZK1 and NHERF4/PDZK2/IKEPP, have been demonstrated to possess sequence homology with NHERF1 and NHERF2 (11-14). However, unlike NHERF1 and NHERF2, which are comprised of two tandem PDZ domains flanked by a C-terminal ezrin/radixin/moesin binding domain, NHERF3 and NHERF4 consist of four PDZ domains but no other proteinprotein interacting domains (12). NHERF3 was initially identified by a yeast two-hybrid screen from a human kidney cDNA library using the membrane-associated protein MAP17, as bait (12). NHERF3 is expressed in the brush border of epithelial cells of the kidney proximal tubule and the small intestine (12). NHERF3 associates with and, in a few cases, has been shown to regulate the activity of multiple apical membrane ion transporters including the cystic fibrosis transmembrane regulator (CFTR), urate anion exchanger 1 (URAT1), sodium-phosphate cotransporter type IIa (NaP i IIa), proton-coupled peptide transporter (PEPT2), and organic cation/carnitine cotransporter (OCTN2) (15-19). Furthermore, NHERF3 directly binds the C terminus of NHE3 (20). Recent studies have begun evaluating the effect of NHERF3 on mouse intestinal Na ϩ and Cl Ϫ transport. Basal electroneutral sodium absorption was decreased by Ͼ40% in the NHERF3 null mouse jejunum (21) and by Ͼ80% in the colon (22). In addition, Cinar * This work was supported, in whole or in part, by National Institutes of Health Grants R01-DK26523, R01-DK61765, PO1-DK72084, K01-DK080930, and R24-DK64388 (The Hopkins Basic Research Digestive Diseases Development Core Center) from the NIDDK. This work was also supported by Grant T32-DK07632 from The Hopkins Center for Epithelial Disorders.

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Section: Discussionmentioning

confidence: 79%

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

Zachos¹,

Li²,

Kovbasnjuk³

et al. 2009

Journal of Biological Chemistry

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“…It seems likely that these other regions of PDZK1 interact with additional cellular components to properly control SR-BI activity. It is possible that the phosphorylated C terminus of PDZK1 (35) or the other three PDZ domains (PDZ2-PDZ4) and their binding partners may play a critical role in regulating SR-BI. Additional putative PDZK1-interacting components apparently are either not present in limiting amounts or cannot interact with PDZK1 efficiently unless it is bound to SR-BI, because overexpression of PDZK1 protein in the liver of WT mice had virtually no effect on normal hepatic SR-BI levels and lipoprotein metabolism (no dominant negative phenotypes observed; the excess PDZK1 did not titrate out other critical components).…”

Section: Discussionmentioning

confidence: 99%

“…The role(s) of these domains in the regulation of hepatic SR-BI are unknown. Nakamura et al (35) have shown that the C terminus and the phosphorylation of PDZK1 are required for optimal PDZK1 transgene-mediated induction of increased SR-BI protein levels in cultured cells. It is possible that PDZ2, PDZ3, and/or PDZ4 bind to other, as yet unidentified, cellular components involved in SR-BI regulation.…”

mentioning

confidence: 99%

Overexpression of the PDZ1 Domain of PDZK1 Blocks the Activity of Hepatic Scavenger Receptor, Class B, Type I by Altering Its Abundance and Cellular Localization

Fenske

Yesilaltay

Pal

et al. 2008

Journal of Biological Chemistry

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PDZK1 is a four-PDZ domain-containing scaffold protein that, via its first PDZ domain (PDZ1), binds to the C terminus of the high density lipoprotein (HDL) receptor scavenger receptor, class B, type I (SR-BI). Abolishing PDZK1 expression in PDZK1 knock-out (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally large HDL particles. Here we show that, although hepatic overexpression of PDZK1 restored normal SR-BI protein abundance and function in PDZK1 KO mice, hepatic overexpression of only the PDZ1 domain was not sufficient to restore normal SR-BI function. In wild-type mice, overexpression of the PDZ1 domain overcame the activity of the endogenous hepatic PDZK1, resulting in a 75% reduction in hepatic SR-BI protein levels and intracellular mislocalization of the remaining SR-BI. As a consequence, the plasma lipoproteins in PDZ1 transgenic mice resembled those in PDZK1 KO mice (hypercholesterolemia due to large HDL). These results indicate that the PDZ1 domain can control the abundance and localization, and therefore the function, of hepatic SR-BI and that structural features of PDZK1 in addition to its SR-BI-binding PDZ1 domain are required for normal hepatic SR-BI regulation.The high density lipoprotein (HDL) 3 receptor SR-BI (scavenger receptor, class B, type I) plays a key role in lipoprotein metabolism (1) by mediating the cellular uptake of cholesteryl esters from HDL and other lipoproteins into cells (2-7) via a mechanism called selective lipid uptake (3, 8 -10). SR-BI also mediates bidirectional flux of unesterified cholesterol between cells and lipoproteins (11)(12)(13)(14).Most in vivo analyses of the physiological function of SR-BI have been conducted in mice. SR-BI is highly expressed in the liver and steroidogenic tissues (adrenal gland, ovary, and testis), which exhibit the highest levels of HDL cholesterol uptake (3). Experimental manipulations of murine SR-BI expression (e.g. hepatic overexpression, homozygous null gene knock-out) can lead to changes in total plasma cholesterol levels, the ratio of plasma unesterified to total cholesterol, HDL structure, biliary cholesterol secretion, the amounts of cholesterol stored in steroidogenic tissues, and susceptibility to atherosclerosis (15-27). Homozygous null SR-BI knock-out mice exhibit abnormally elevated (ϳ2.2-fold) plasma cholesterol in large HDL particles with a unesterified cholesterol/total cholesterol ratio roughly double that of wild-type (WT) mice (19,52). This dyslipidemia is associated with female infertility and defects in the maturation and/or structure as well as reductions in the survival times of red blood cells (21,28,29,30).To date, only one intracellular protein has been shown to interact directly with and influence the function of SR-BI (31). This protein, PDZK1, regulates SR-BI expression in a tissuespecific, post-transcriptional manner (32). PDZK1 is a scaffold protein containing four PDZ protein interaction domains (Fig. 1A...

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“…It is well known that CEs, in specialized tissues such as the adrenal cortex and liver ( 56 ), are taken up directly from HDLs ( 57 ) by a plasma-membrane scavenger receptor protein (SR-B1) in rodents ( 49 ), and CLA-1 in humans ( 58 ). Furthermore, a selective uptake of CE-HDLs by SR-B1 has been described in rapidly proliferating tumor cells ( 50,58,59 ).…”

Section: Discussionmentioning

confidence: 99%

Role of HDL in cholesteryl ester metabolism of lipopolysaccharide-activated P388D1 macrophages

Uda

Spolitu

Angius

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org hallmark of atherosclerosis. Similar changes are present in chronic metabolic diseases (hypercholesterolemia, insulin resistance, diabetes, etc.) ( 4 ), and have been described in other disorders such as cancer ( 5-9 ) and infections ( 10 ). Probably, accumulation of CEs serves as a reservoir of cholesterol for an enhanced membrane biogenesis during sustained proliferation.During acute infections the body undergoes several metabolic changes ( 11,12 ), among which plasma lipid alterations are prominent and related to a shift in energetic requirements (increased triglycerides and fatty acids) ( 13,14 ) or to structural modifi cation of LDLs ( 15 ) and HDLs ( 16,17 ). The infection-related decrease in C-HDLs observed in all species is ascribed to a reduction of proteins involved in reverse cholesterol transport ( 18,19 ), supposedly induced by infl ammatory molecules secreted from immune cells activated by the microbial stimulus ( 16 ). Thus, during infection, an ineffi cient removal of cholesterol from the arteries may contribute toward eliciting a lipid overload of macrophages and transformation of the former into foam cells ( 19 ). For this reason, infections have been considered as a serious risk factor for the development or worsening of atherosclerosis (20)(21)(22). Epidemiological fi ndings support this correlation, with acute vascular accidents (myocardial infarction, ictus, etc.) being described during acute and chronic infections. Carotid plaques have been observed in patients with periodontal diseases ( 23, 24 ) and other chronic infections ( 25,26 ).

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Regulation of SR-BI protein levels by phosphorylation of its associated protein, PDZK1

Cited by 47 publications

References 36 publications

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

NHERF3 (PDZK1) Contributes to Basal and Calcium Inhibition of NHE3 Activity in Caco-2BBe Cells

Overexpression of the PDZ1 Domain of PDZK1 Blocks the Activity of Hepatic Scavenger Receptor, Class B, Type I by Altering Its Abundance and Cellular Localization

Role of HDL in cholesteryl ester metabolism of lipopolysaccharide-activated P388D1 macrophages

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