Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LNX is a RING finger and PDZ domain containing protein that interacts with the cell fate determinant Numb. To investigate the function of LNX, we tested its RING finger domain for ubiquitin ligase activity. The isolated RING finger domain was able to function as an E2-dependent, E3 ubiquitin ligase in vitro and mutation of a conserved cysteine residue within the RING domain abolished its activity, indicating that LNX is the first described PDZ domain-containing member of the E3 ubiquitin ligase family. We have identified Numb as a substrate of LNX E3 activity in vitro and in vivo. In addition to the RING finger, a region of LNX, including the Numb PTB domain-binding site and the first PDZ domain, is required for Numb ubiquitylation. Expression of wild-type but not mutant LNX causes proteasome-dependent degradation of Numb and can enhance Notch signalling. These results suggest that the levels of mammalian Numb protein and therefore, by extension, the processes of asymmetric cell division and cell fate determination may be regulated by ubiquitin-dependent proteolysis.
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PMID:LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. 1178 29

Scavenger receptor class B, type I (SR-BI) is the high density lipoprotein (HDL) receptor essential for hepatic uptake of HDL cholesterol. SR-BI was shown to impact plasma HDL levels and be anti-atherogenic. Thus, the ability to regulate hepatic SR-BI may allow for the modulation of plasma HDL cholesterol and progression of atherosclerosis. However, regulation of SR-BI in liver is not well understood. Recently, the PDZ domain containing protein PDZK1 was shown to interact with SR-BI and may serve an essential role in SR-BI cell surface expression. Here we identify an in vivo PDZK1-interacting protein that we named small PDZK1-associated protein (SPAP; also known as DD96/MAP17). Unexpectedly, we found that hepatic overexpression of SPAP in mice resulted in liver deficiency of PDZK1. The absence of PDZK1 in SPAP transgenic mice resulted in a deficiency of SR-BI in liver and markedly increased plasma HDL. Metabolic labeling experiments showed that the proteasome plays a role in the turnover of newly synthesized PDZK1, but that SPAP overexpression in liver increased PDZK1 turnover in an alternate, proteasome-independent pathway. Thus, SPAP may be an endogenous regulator of cellular PDZK1 levels by regulating PDZK1 turnover.
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PMID:Identification of small PDZK1-associated protein, DD96/MAP17, as a regulator of PDZK1 and plasma high density lipoprotein levels. 1275 12

Fibrate drugs improve cardiovascular health by lowering plasma triglycerides, normalize low density lipoprotein levels, and raise high density lipoprotein (HDL) levels in patients with dyslipidemias. The HDL-raising effect of fibrates has been shown to be due in part to an increase in human apolipoprotein AI gene expression. However, it has recently been shown that fibrates can affect HDL metabolism in mouse by significantly decreasing hepatic levels of the HDL receptor scavenger receptor B-I (SR-BI) and the PDZ domain containing protein PDZK1. PDZK1 is essential for maintaining hepatic SR-BI levels. Therefore, decreased SR-BI might be secondary to decreased PDZK1, but the mechanism by which fibrates lower SR-BI has not been elucidated. Here we show that feeding PDZK1-deficient mice fenofibrate resulted in the near absence of SR-BI in liver, definitively demonstrating that the effect of fenofibrate on SR-BI is PDZK1-independent. Metabolic labeling experiments in primary hepatocytes from fenofibrate-fed mice demonstrated that fenofibrate enhanced the degradation of SR-BI in a post-endoplasmic reticulum compartment. Moreover, fenofibrate-induced degradation of SR-BI was independent of the proteasome, calpain protease, or the lysosome, and antioxidants did not inhibit fenofibrate-induced degradation of SR-BI. Using metabolic labeling coupled with cell surface biotinylation assays, fenofibrate did not inhibit SR-BI trafficking to the plasma membrane. Together, the data support a model in which fenofibrate enhances the degradation of SR-BI in a post-ER, post-plasma membrane compartment. The further elucidation of this novel degradation pathway may provide new insights into the physiological and pathophysiological regulation of hepatic SR-BI.
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PMID:Fenofibrate induces a novel degradation pathway for scavenger receptor B-I independent of PDZK1. 1583 86