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The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing
The low‐density lipoprotein receptor‐related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the β‐amyloid precursor protein (APP) interacts with LRP and that this association may i...
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| Published in: | The EMBO journal 2002-11, Vol.21 (21), p.5691-5700 |
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| container_end_page | 5700 |
| container_issue | 21 |
| container_start_page | 5691 |
| container_title | The EMBO journal |
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| creator | Pietrzik, Claus U. Busse, Tracy Merriam, David E. Weggen, Sascha Koo, Edward H. |
| description | The low‐density lipoprotein receptor‐related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the β‐amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid β‐protein (Aβ). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Aβ production, APP secretion, APP internalization, turnover of full‐length APP and stability of APP C‐terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504–4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Aβ production, through interactions of the cytosolic domains. |
| doi_str_mv | 10.1093/emboj/cdf568 |
| format | article |
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Studies have shown that the β‐amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid β‐protein (Aβ). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Aβ production, APP secretion, APP internalization, turnover of full‐length APP and stability of APP C‐terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504–4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Aβ production, through interactions of the cytosolic domains.</description><identifier>ISSN: 0261-4189</identifier><identifier>ISSN: 1460-2075</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.1093/emboj/cdf568</identifier><identifier>PMID: 12411487</identifier><identifier>CODEN: EMJODG</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Alzheimer's disease ; Amyloid beta-Protein Precursor - metabolism ; amyloid β-peptide ; Animals ; Blotting, Western ; Cell Line ; Cytoplasm - metabolism ; DNA, Complementary ; EMBO20 ; EMBO24 ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts - metabolism ; Low Density Lipoprotein Receptor-Related Protein-1 - chemistry ; Low Density Lipoprotein Receptor-Related Protein-1 - genetics ; Low Density Lipoprotein Receptor-Related Protein-1 - physiology ; low-density lipoprotein receptor-related protein ; Mice ; Precipitin Tests ; processing ; Protein Processing, Post-Translational ; trafficking ; β-amyloid precursor protein</subject><ispartof>The EMBO journal, 2002-11, Vol.21 (21), p.5691-5700</ispartof><rights>European Molecular Biology Organization 2002</rights><rights>Copyright © 2002 European Molecular Biology Organization</rights><rights>Copyright Oxford University Press(England) Nov 01, 2002</rights><rights>Copyright © 2002 European Molecular Biology Organization 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6475-b90f177d0dc4d747ef4d4c34ddff609c6d8bea5c6a63cb31fb535fecf970bf6b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC131065/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC131065/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12411487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pietrzik, Claus U.</creatorcontrib><creatorcontrib>Busse, Tracy</creatorcontrib><creatorcontrib>Merriam, David E.</creatorcontrib><creatorcontrib>Weggen, Sascha</creatorcontrib><creatorcontrib>Koo, Edward H.</creatorcontrib><title>The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing</title><title>The EMBO journal</title><addtitle>EMBO J</addtitle><addtitle>EMBO J</addtitle><description>The low‐density lipoprotein receptor‐related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the β‐amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid β‐protein (Aβ). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Aβ production, APP secretion, APP internalization, turnover of full‐length APP and stability of APP C‐terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504–4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Aβ production, through interactions of the cytosolic domains.</description><subject>Alzheimer's disease</subject><subject>Amyloid beta-Protein Precursor - metabolism</subject><subject>amyloid β-peptide</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Cytoplasm - metabolism</subject><subject>DNA, Complementary</subject><subject>EMBO20</subject><subject>EMBO24</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Fibroblasts - metabolism</subject><subject>Low Density Lipoprotein Receptor-Related Protein-1 - chemistry</subject><subject>Low Density Lipoprotein Receptor-Related Protein-1 - genetics</subject><subject>Low Density Lipoprotein Receptor-Related Protein-1 - physiology</subject><subject>low-density lipoprotein receptor-related protein</subject><subject>Mice</subject><subject>Precipitin Tests</subject><subject>processing</subject><subject>Protein Processing, Post-Translational</subject><subject>trafficking</subject><subject>β-amyloid precursor protein</subject><issn>0261-4189</issn><issn>1460-2075</issn><issn>1460-2075</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNqFks1v1DAQxSMEokvhxhUUceBEqB1_JQcObWkLqwVWYhFHy7HHWy9JHOwE2P-eLFkt5UNwsuT3e-OZeU6Shxg9x6gkJ9BUfnOijWW8uJXMMOUoy5Fgt5MZyjnOKC7Ko-RejBuEECsEvpsc4ZxiTAsxS2B1Dane9r6rVWycTo1vlGtTb9N-VBYvF2kADV3vQxagVj2YtAu-h5EJsB52NzFthrp3XQ1p7KGL6aidLpc7TkOMrl3fT-5YVUd4sD-Pkw-XF6vzV9ni3dXr89NFpjkVLKtKZLEQBhlNjaACLDVUE2qMtRyVmpuiAsU0V5zoimBbMcIsaFsKVFlekePkxVS3G6oGjIa2D6qWXXCNClvplZO_Kq27lmv_RWKCEWej_-neH_znAWIvGxc11LVqwQ9Ripwzykn-XxAXHLGc78Anv4EbP4R2XILEJcsZwQKP0LMJ0sHHGMAeOsZI7kKWP0KWU8gj_vjmlD_hfaojwCbgq6th-89i8uLN2VywkopiN342-eJoadcQbjT790YeTXyr-iHA4aE_6rnxX3w7yCp8klwQweTHt1fy_eryLJ_zuVyS78Zx4Ng</recordid><startdate>20021101</startdate><enddate>20021101</enddate><creator>Pietrzik, Claus U.</creator><creator>Busse, Tracy</creator><creator>Merriam, David E.</creator><creator>Weggen, Sascha</creator><creator>Koo, Edward H.</creator><general>John Wiley & Sons, Ltd</general><general>Nature Publishing Group UK</general><general>Blackwell Publishing Ltd</general><general>Oxford University Press</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PCBAR</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20021101</creationdate><title>The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing</title><author>Pietrzik, Claus U. ; Busse, Tracy ; Merriam, David E. ; Weggen, Sascha ; Koo, Edward H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6475-b90f177d0dc4d747ef4d4c34ddff609c6d8bea5c6a63cb31fb535fecf970bf6b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Alzheimer's disease</topic><topic>Amyloid beta-Protein Precursor - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The EMBO journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pietrzik, Claus U.</au><au>Busse, Tracy</au><au>Merriam, David E.</au><au>Weggen, Sascha</au><au>Koo, Edward H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing</atitle><jtitle>The EMBO journal</jtitle><stitle>EMBO J</stitle><addtitle>EMBO J</addtitle><date>2002-11-01</date><risdate>2002</risdate><volume>21</volume><issue>21</issue><spage>5691</spage><epage>5700</epage><pages>5691-5700</pages><issn>0261-4189</issn><issn>1460-2075</issn><eissn>1460-2075</eissn><coden>EMJODG</coden><abstract>The low‐density lipoprotein receptor‐related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the β‐amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid β‐protein (Aβ). In this report, we provide evidence that LRP regulates trafficking of intracellular proteins independently of its lipoprotein receptor functions. We show that in the absence of LRP, Aβ production, APP secretion, APP internalization, turnover of full‐length APP and stability of APP C‐terminal fragments are affected. Importantly, these changes are not APP isoform dependent. Using deletion constructs, the critical region in LRP that modulates APP processing was mapped to a seven peptide domain around the second NPXY domain (residues 4504–4510). Therefore, we propose a model by which LRP functionally modulates APP processing, including those steps critical for Aβ production, through interactions of the cytosolic domains.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>12411487</pmid><doi>10.1093/emboj/cdf568</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Alzheimer's disease Amyloid beta-Protein Precursor - metabolism amyloid β-peptide Animals Blotting, Western Cell Line Cytoplasm - metabolism DNA, Complementary EMBO20 EMBO24 Enzyme-Linked Immunosorbent Assay Fibroblasts - metabolism Low Density Lipoprotein Receptor-Related Protein-1 - chemistry Low Density Lipoprotein Receptor-Related Protein-1 - genetics Low Density Lipoprotein Receptor-Related Protein-1 - physiology low-density lipoprotein receptor-related protein Mice Precipitin Tests processing Protein Processing, Post-Translational trafficking β-amyloid precursor protein |
| title | The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing |
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