Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101
The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this stud...
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Veröffentlicht in: | Molecular cancer research 2018-05, Vol.16 (5), p.909-919 |
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description | The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this study, it was mechanistically determined that Autophagy-related 101 (ATG101), essential for mammalian autophagy, physically interacts with the CTD of PTCH1 and connects it to the ULK complex, which stimulates the autophagy machinery in response to changes in nutrient availability. This interaction results in a blockade of basal autophagic flux and accumulation of autophagosomes with undegraded cargo. Remarkably, this function of PTCH1 is independent of its repressive activity on SMO, as shown in SMO-deficient cells or in the presence of a SMO inhibitor, but is opposed by Sonic Hedgehog (SHH). These findings reveal a novel noncanonical function of PTCH1 that limits autophagy, mediated by ATG101, which could have therapeutic implications in Hh-dependent cancers.
Loss-of-function of the tumor suppressor Patched1 might promote cancer cell fitness by increasing autophagic flux in response to metabolic or environmental stresses.
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doi_str_mv | 10.1158/1541-7786.MCR-17-0597 |
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Loss-of-function of the tumor suppressor Patched1 might promote cancer cell fitness by increasing autophagic flux in response to metabolic or environmental stresses.
.</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-17-0597</identifier><identifier>PMID: 29453315</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Animals ; Apoptosis ; Autophagy ; Autophagy-Related Proteins - metabolism ; Cancer ; Environmental stress ; Fibroblasts ; Fitness ; Fluctuations ; Flux ; Hedgehog protein ; Hedgehog Proteins - metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Metabolic flux ; Mice ; Nutrient availability ; Patched-1 Receptor - metabolism ; Phagocytosis ; Phagosomes ; Protein Domains ; Signal Transduction ; Transcription Factors - metabolism ; Tumor suppressor genes ; Tumors ; Vesicular Transport Proteins - metabolism</subject><ispartof>Molecular cancer research, 2018-05, Vol.16 (5), p.909-919</ispartof><rights>2018 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc May 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c557t-8ba54d3f768bc4f0b07e47df4b99c304cb07a20ec9c4ab3b7e1a5e21cf5d0a913</citedby><cites>FETCH-LOGICAL-c557t-8ba54d3f768bc4f0b07e47df4b99c304cb07a20ec9c4ab3b7e1a5e21cf5d0a913</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29453315$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Xiaole</creatorcontrib><creatorcontrib>Morales-Alcala, Cintli C</creatorcontrib><creatorcontrib>Riobo-Del Galdo, Natalia A</creatorcontrib><title>Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this study, it was mechanistically determined that Autophagy-related 101 (ATG101), essential for mammalian autophagy, physically interacts with the CTD of PTCH1 and connects it to the ULK complex, which stimulates the autophagy machinery in response to changes in nutrient availability. This interaction results in a blockade of basal autophagic flux and accumulation of autophagosomes with undegraded cargo. Remarkably, this function of PTCH1 is independent of its repressive activity on SMO, as shown in SMO-deficient cells or in the presence of a SMO inhibitor, but is opposed by Sonic Hedgehog (SHH). These findings reveal a novel noncanonical function of PTCH1 that limits autophagy, mediated by ATG101, which could have therapeutic implications in Hh-dependent cancers.
Loss-of-function of the tumor suppressor Patched1 might promote cancer cell fitness by increasing autophagic flux in response to metabolic or environmental stresses.
.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Autophagy-Related Proteins - metabolism</subject><subject>Cancer</subject><subject>Environmental stress</subject><subject>Fibroblasts</subject><subject>Fitness</subject><subject>Fluctuations</subject><subject>Flux</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - metabolism</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Metabolic flux</subject><subject>Mice</subject><subject>Nutrient availability</subject><subject>Patched-1 Receptor - metabolism</subject><subject>Phagocytosis</subject><subject>Phagosomes</subject><subject>Protein Domains</subject><subject>Signal Transduction</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor suppressor genes</subject><subject>Tumors</subject><subject>Vesicular Transport Proteins - metabolism</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtv1DAUhS0EomXgJ4AssWGT1tePcbJBGqYPRioCVWVtHOdmJlViT2MH6L_HUacVsLJ1_d2j43MIeQvsBECVp6AkFFqXy5Mv6-sCdMFUpZ-RY1BKFwK4ej7fD8wReRXjLWOcgV6-JEe8kkoIUMfkx2pKYb-z287Ri376TTeRXuN26m3Chtb3dOMTjtalLnj6CdMvRE_TDum6yPOh87anZ2Gwnaehpd9WN-vP52dArW_o6uYSGLwmL1rbR3xzOBfk-8V5poqrr5eb9eqqcNlwKsraKtmIVi_L2smW1Uyj1E0r66pygkmXB5YzdJWTtha1RrAKObhWNcxWIBbk44PufqoHbBz6NNre7MdusOO9CbYz_774bme24adRleBcySzw4SAwhrsJYzJDFx32vfUYpmg4Y9mHKkud0ff_obdhGnMUMyX4Moec410Q9UC5McQ4YvtkBpiZOzRzP2bux-QODWgzd5j33v39k6etx9LEH2ColvM</recordid><startdate>20180501</startdate><enddate>20180501</enddate><creator>Chen, Xiaole</creator><creator>Morales-Alcala, Cintli C</creator><creator>Riobo-Del Galdo, Natalia A</creator><general>American Association for Cancer Research Inc</general><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>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180501</creationdate><title>Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101</title><author>Chen, Xiaole ; Morales-Alcala, Cintli C ; Riobo-Del Galdo, Natalia A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c557t-8ba54d3f768bc4f0b07e47df4b99c304cb07a20ec9c4ab3b7e1a5e21cf5d0a913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Autophagy-Related Proteins - metabolism</topic><topic>Cancer</topic><topic>Environmental stress</topic><topic>Fibroblasts</topic><topic>Fitness</topic><topic>Fluctuations</topic><topic>Flux</topic><topic>Hedgehog protein</topic><topic>Hedgehog Proteins - metabolism</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Metabolic flux</topic><topic>Mice</topic><topic>Nutrient availability</topic><topic>Patched-1 Receptor - metabolism</topic><topic>Phagocytosis</topic><topic>Phagosomes</topic><topic>Protein Domains</topic><topic>Signal Transduction</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor suppressor genes</topic><topic>Tumors</topic><topic>Vesicular Transport Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Xiaole</creatorcontrib><creatorcontrib>Morales-Alcala, Cintli C</creatorcontrib><creatorcontrib>Riobo-Del Galdo, Natalia A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Xiaole</au><au>Morales-Alcala, Cintli C</au><au>Riobo-Del Galdo, Natalia A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2018-05-01</date><risdate>2018</risdate><volume>16</volume><issue>5</issue><spage>909</spage><epage>919</epage><pages>909-919</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this study, it was mechanistically determined that Autophagy-related 101 (ATG101), essential for mammalian autophagy, physically interacts with the CTD of PTCH1 and connects it to the ULK complex, which stimulates the autophagy machinery in response to changes in nutrient availability. This interaction results in a blockade of basal autophagic flux and accumulation of autophagosomes with undegraded cargo. Remarkably, this function of PTCH1 is independent of its repressive activity on SMO, as shown in SMO-deficient cells or in the presence of a SMO inhibitor, but is opposed by Sonic Hedgehog (SHH). These findings reveal a novel noncanonical function of PTCH1 that limits autophagy, mediated by ATG101, which could have therapeutic implications in Hh-dependent cancers.
Loss-of-function of the tumor suppressor Patched1 might promote cancer cell fitness by increasing autophagic flux in response to metabolic or environmental stresses.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>29453315</pmid><doi>10.1158/1541-7786.MCR-17-0597</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Apoptosis Autophagy Autophagy-Related Proteins - metabolism Cancer Environmental stress Fibroblasts Fitness Fluctuations Flux Hedgehog protein Hedgehog Proteins - metabolism HEK293 Cells HeLa Cells Humans Metabolic flux Mice Nutrient availability Patched-1 Receptor - metabolism Phagocytosis Phagosomes Protein Domains Signal Transduction Transcription Factors - metabolism Tumor suppressor genes Tumors Vesicular Transport Proteins - metabolism |
title | Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101 |
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