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• W2794365093 endingPage "1293" @default.
• W2794365093 startingPage "1271" @default.
• W2794365093 abstract "Autosomal-dominant, missense mutations in the leucine-rich repeat protein kinase 2 (LRRK2) gene are the most common genetic predisposition to develop Parkinson's disease (PD). LRRK2 kinase activity is increased in several pathogenic mutations (N1437H, R1441C/G/H, Y1699C, G2019S), implicating hyperphosphorylation of a substrate in the pathogenesis of the disease. Identification of the downstream targets of LRRK2 is a crucial endeavor in the field to understand LRRK2 pathway dysfunction in the disease. We have identified the signaling adapter protein p62/SQSTM1 as a novel endogenous interacting partner and a substrate of LRRK2. Using mass spectrometry and phospho-specific antibodies, we found that LRRK2 phosphorylates p62 on Thr138 in vitro and in cells. We found that the pathogenic LRRK2 PD-associated mutations (N1437H, R1441C/G/H, Y1699C, G2019S) increase phosphorylation of p62 similar to previously reported substrate Rab proteins. Notably, we found that the pathogenic I2020T mutation and the risk factor mutation G2385R displayed decreased phosphorylation of p62. p62 phosphorylation by LRRK2 is blocked by treatment with selective LRRK2 inhibitors in cells. We also found that the amino-terminus of LRRK2 is crucial for optimal phosphorylation of Rab7L1 and p62 in cells. LRRK2 phosphorylation of Thr138 is dependent on a p62 functional ubiquitin-binding domain at its carboxy-terminus. Co-expression of p62 with LRRK2 G2019S increases the neurotoxicity of this mutation in a manner dependent on Thr138. p62 is an additional novel substrate of LRRK2 that regulates its toxic biology, reveals novel signaling nodes and can be used as a pharmacodynamic marker for LRRK2 kinase activity." @default.
• W2794365093 created "2018-03-29" @default.
• W2794365093 creator A5000257912 @default.
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• W2794365093 creator A5060418599 @default.
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• W2794365093 creator A5086770264 @default.
• W2794365093 date "2018-04-09" @default.
• W2794365093 modified "2023-10-01" @default.
• W2794365093 title "P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity" @default.
• W2794365093 cites W1486793962 @default.
• W2794365093 cites W152096304 @default.
• W2794365093 cites W1527671059 @default.
• W2794365093 cites W1564467880 @default.
• W2794365093 cites W1743712153 @default.
• W2794365093 cites W1967900265 @default.
• W2794365093 cites W1969362677 @default.
• W2794365093 cites W1969608755 @default.
• W2794365093 cites W1971196542 @default.
• W2794365093 cites W1974515407 @default.
• W2794365093 cites W1977391806 @default.
• W2794365093 cites W1977709885 @default.
• W2794365093 cites W1982396115 @default.
• W2794365093 cites W1986961354 @default.
• W2794365093 cites W1987155530 @default.
• W2794365093 cites W1992365739 @default.
• W2794365093 cites W1993450321 @default.
• W2794365093 cites W1993547586 @default.
• W2794365093 cites W1993942749 @default.
• W2794365093 cites W1994444930 @default.
• W2794365093 cites W1996424480 @default.
• W2794365093 cites W1999387506 @default.
• W2794365093 cites W2002260194 @default.
• W2794365093 cites W2006875797 @default.
• W2794365093 cites W2007442181 @default.
• W2794365093 cites W2021976306 @default.
• W2794365093 cites W2022675211 @default.
• W2794365093 cites W2026460862 @default.
• W2794365093 cites W2026938943 @default.
• W2794365093 cites W2032888222 @default.
• W2794365093 cites W2033827101 @default.
• W2794365093 cites W2037006420 @default.
• W2794365093 cites W2039073478 @default.
• W2794365093 cites W2039445258 @default.
• W2794365093 cites W2040044504 @default.
• W2794365093 cites W2042213574 @default.
• W2794365093 cites W2043274355 @default.
• W2794365093 cites W2046398127 @default.
• W2794365093 cites W2048337652 @default.
• W2794365093 cites W2050902269 @default.
• W2794365093 cites W2055432326 @default.
• W2794365093 cites W2055632128 @default.
• W2794365093 cites W2056164308 @default.
• W2794365093 cites W2063127941 @default.
• W2794365093 cites W2069115784 @default.
• W2794365093 cites W2071174827 @default.
• W2794365093 cites W2072216745 @default.
• W2794365093 cites W2073861040 @default.
• W2794365093 cites W2074383422 @default.
• W2794365093 cites W2075407995 @default.
• W2794365093 cites W2078955175 @default.
• W2794365093 cites W2079786231 @default.
• W2794365093 cites W2080679736 @default.
• W2794365093 cites W2080693065 @default.
• W2794365093 cites W2081106067 @default.
• W2794365093 cites W2084935470 @default.
• W2794365093 cites W2087360216 @default.
• W2794365093 cites W2089025542 @default.
• W2794365093 cites W2089522371 @default.
• W2794365093 cites W2094992876 @default.
• W2794365093 cites W2096905204 @default.
• W2794365093 cites W2099111846 @default.
• W2794365093 cites W2099677820 @default.
• W2794365093 cites W2100300726 @default.
• W2794365093 cites W2100894616 @default.
• W2794365093 cites W2103275390 @default.
• W2794365093 cites W2106006107 @default.
• W2794365093 cites W2107114877 @default.
• W2794365093 cites W2109186157 @default.
• W2794365093 cites W2110157421 @default.
• W2794365093 cites W2110742691 @default.
• W2794365093 cites W2112286366 @default.
• W2794365093 cites W2113282929 @default.
• W2794365093 cites W2116200652 @default.
• W2794365093 cites W2116709932 @default.
• W2794365093 cites W2116883703 @default.
• W2794365093 cites W2120262230 @default.
• W2794365093 cites W2123609677 @default.
• W2794365093 cites W2126238482 @default.
• W2794365093 cites W2128247060 @default.
• W2794365093 cites W2128471322 @default.
• W2794365093 cites W2130168483 @default.
• W2794365093 cites W2134829539 @default.
• W2794365093 cites W2136216054 @default.

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