Nat Commun:RNF167靶向降解CASTOR1激活mTORC1促进肿瘤的发生发展

2021-02-25 xiaozeng MedSci原创

在约10%的癌症中丝氨酸/苏氨酸激酶AKT发生了突变,这很大程度的说明了其在癌症中的致癌作用。除了AKT基因突变外,生长因子上游信号通路的失调常常能够激活癌细胞中的AKT。

在约10%的癌症中丝氨酸/苏氨酸激酶AKT发生了突变,这很大程度的说明了其在癌症中的致癌作用。除了AKT基因突变外,生长因子上游信号通路的失调常常能够激活癌细胞中的AKT。

GSK3β、FOXO和TSC2是AKT的三个主要的下游基因,其能够介导AKT对不同刺激的响应并行使多种功能。既往研究显示,AKT介导的TSC2磷酸化和抑制作用已被认为是AKT激活mTORC1(雷帕霉素复合物1)的主要机制。


mTORC1是细胞响应生长因子和营养素进行细胞增殖的中心调控因子,其在癌症中表达失调。精氨酸能够激活mTORC1。

相关机制示意图

CASTOR1(mTORC1亚基1)是一种新发现的胞质精氨酸传感器,其可对精氨酸响应并调节mTORC1的活性。有趣的是,高水平的CASTOR1蛋白会抑制AAS(包括精氨酸)对mTORC1的激活。由于癌细胞常处于低营养水平状态,因此可能存在另一种机制来调控CASTOR1的表达。


在该研究中,研究人员发现E29泛素连接酶RNF167能够对CASTOR1进行K29连接的多泛素化和降解。此外,AKT能够介导CASTOR1 S14位点的磷酸化,显著增加其与RNF167的结合,促进其泛素化和降解,并降低其对MIOS的亲和力,从而导致mTORC1的激活。因此说明AKT可通过TSC2和CASTOR1依赖性途径来激活mTORC1。

RNF167介导的泛素化和AKT1介导的磷酸化促进乳腺癌的发生发展

进一步的研究显示,几种具有较高CASTOR1表达的细胞类型对精氨酸的调节并不敏感。值得注意的是,AKT和RNF167介导的CASTOR1降解能够激活独立于精氨酸的mTORC1,并最终促进乳腺癌的发生发展。


总而言之,该研究结果揭示了mTORC1的相关调节机制,并将RNF167鉴定为mTORC1失调相关疾病的治疗靶标。


原始出处:

Li, T., Wang, X., Ju, E. et al. RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation. Nat Commun 12, 1055 (16 February 2021).

 



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    2021-07-24 liye789132251
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    2021-08-19 ay2000fy
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  5. [GetPortalCommentsPageByObjectIdResponse(id=1712709, encodeId=74531e127098e, content=<a href='/topic/show?id=9a1c289680' target=_blank style='color:#2F92EE;'>#AST#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2896, encryptionId=9a1c289680, topicName=AST)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8b9831894722, createdName=ms24272190615788285182, createdTime=Wed Jul 07 21:02:15 CST 2021, time=2021-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885015, encodeId=b4f6188501557, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jul 24 08:02:15 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1927989, encodeId=09fb192e98991, content=<a href='/topic/show?id=ed8712e399b' target=_blank style='color:#2F92EE;'>#NF1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12739, encryptionId=ed8712e399b, topicName=NF1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f34c147, createdName=ay2000fy, createdTime=Thu Aug 19 10:02:15 CST 2021, time=2021-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2030810, encodeId=54b020308108b, content=<a href='/topic/show?id=71353e8964f' target=_blank style='color:#2F92EE;'>#发生发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37896, encryptionId=71353e8964f, topicName=发生发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=346311, createdName=wgsun, createdTime=Fri Apr 09 12:02:15 CST 2021, time=2021-04-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087933, encodeId=10e3208e93387, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Mon Nov 01 17:02:15 CST 2021, time=2021-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=954944, encodeId=afb59549443e, content=已看,还可以。, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1bc65476534, createdName=ms6000001015893838, createdTime=Wed Apr 07 16:22:48 CST 2021, time=2021-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1418405, encodeId=8133141840591, content=<a href='/topic/show?id=2cc91232947' target=_blank style='color:#2F92EE;'>#mTORC1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12329, encryptionId=2cc91232947, topicName=mTORC1)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=59413348493, createdName=雕雕, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624970, encodeId=18b716249e015, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=)]
    2021-11-01 liuli5079
  6. [GetPortalCommentsPageByObjectIdResponse(id=1712709, encodeId=74531e127098e, content=<a href='/topic/show?id=9a1c289680' target=_blank style='color:#2F92EE;'>#AST#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2896, encryptionId=9a1c289680, topicName=AST)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8b9831894722, createdName=ms24272190615788285182, createdTime=Wed Jul 07 21:02:15 CST 2021, time=2021-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885015, encodeId=b4f6188501557, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jul 24 08:02:15 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1927989, encodeId=09fb192e98991, content=<a href='/topic/show?id=ed8712e399b' target=_blank style='color:#2F92EE;'>#NF1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12739, encryptionId=ed8712e399b, topicName=NF1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f34c147, createdName=ay2000fy, createdTime=Thu Aug 19 10:02:15 CST 2021, time=2021-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2030810, encodeId=54b020308108b, content=<a href='/topic/show?id=71353e8964f' target=_blank style='color:#2F92EE;'>#发生发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37896, encryptionId=71353e8964f, topicName=发生发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=346311, createdName=wgsun, createdTime=Fri Apr 09 12:02:15 CST 2021, time=2021-04-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087933, encodeId=10e3208e93387, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Mon Nov 01 17:02:15 CST 2021, time=2021-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=954944, encodeId=afb59549443e, content=已看,还可以。, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1bc65476534, createdName=ms6000001015893838, createdTime=Wed Apr 07 16:22:48 CST 2021, time=2021-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1418405, encodeId=8133141840591, content=<a href='/topic/show?id=2cc91232947' target=_blank style='color:#2F92EE;'>#mTORC1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12329, encryptionId=2cc91232947, topicName=mTORC1)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=59413348493, createdName=雕雕, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624970, encodeId=18b716249e015, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=)]
    2021-04-07 ms6000001015893838

    已看,还可以。

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=1712709, encodeId=74531e127098e, content=<a href='/topic/show?id=9a1c289680' target=_blank style='color:#2F92EE;'>#AST#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2896, encryptionId=9a1c289680, topicName=AST)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8b9831894722, createdName=ms24272190615788285182, createdTime=Wed Jul 07 21:02:15 CST 2021, time=2021-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885015, encodeId=b4f6188501557, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jul 24 08:02:15 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1927989, encodeId=09fb192e98991, content=<a href='/topic/show?id=ed8712e399b' target=_blank style='color:#2F92EE;'>#NF1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12739, encryptionId=ed8712e399b, topicName=NF1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f34c147, createdName=ay2000fy, createdTime=Thu Aug 19 10:02:15 CST 2021, time=2021-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2030810, encodeId=54b020308108b, content=<a href='/topic/show?id=71353e8964f' target=_blank style='color:#2F92EE;'>#发生发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37896, encryptionId=71353e8964f, topicName=发生发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=346311, createdName=wgsun, createdTime=Fri Apr 09 12:02:15 CST 2021, time=2021-04-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087933, encodeId=10e3208e93387, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Mon Nov 01 17:02:15 CST 2021, time=2021-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=954944, encodeId=afb59549443e, content=已看,还可以。, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1bc65476534, createdName=ms6000001015893838, createdTime=Wed Apr 07 16:22:48 CST 2021, time=2021-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1418405, encodeId=8133141840591, content=<a href='/topic/show?id=2cc91232947' target=_blank style='color:#2F92EE;'>#mTORC1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12329, encryptionId=2cc91232947, topicName=mTORC1)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=59413348493, createdName=雕雕, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624970, encodeId=18b716249e015, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=)]
    2021-02-26 雕雕
  8. [GetPortalCommentsPageByObjectIdResponse(id=1712709, encodeId=74531e127098e, content=<a href='/topic/show?id=9a1c289680' target=_blank style='color:#2F92EE;'>#AST#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2896, encryptionId=9a1c289680, topicName=AST)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=8b9831894722, createdName=ms24272190615788285182, createdTime=Wed Jul 07 21:02:15 CST 2021, time=2021-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1885015, encodeId=b4f6188501557, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jul 24 08:02:15 CST 2021, time=2021-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1927989, encodeId=09fb192e98991, content=<a href='/topic/show?id=ed8712e399b' target=_blank style='color:#2F92EE;'>#NF1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12739, encryptionId=ed8712e399b, topicName=NF1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f34c147, createdName=ay2000fy, createdTime=Thu Aug 19 10:02:15 CST 2021, time=2021-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2030810, encodeId=54b020308108b, content=<a href='/topic/show?id=71353e8964f' target=_blank style='color:#2F92EE;'>#发生发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37896, encryptionId=71353e8964f, topicName=发生发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=346311, createdName=wgsun, createdTime=Fri Apr 09 12:02:15 CST 2021, time=2021-04-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087933, encodeId=10e3208e93387, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Mon Nov 01 17:02:15 CST 2021, time=2021-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=954944, encodeId=afb59549443e, content=已看,还可以。, beContent=null, objectType=article, channel=null, level=null, likeNumber=52, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=1bc65476534, createdName=ms6000001015893838, createdTime=Wed Apr 07 16:22:48 CST 2021, time=2021-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1418405, encodeId=8133141840591, content=<a href='/topic/show?id=2cc91232947' target=_blank style='color:#2F92EE;'>#mTORC1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12329, encryptionId=2cc91232947, topicName=mTORC1)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=59413348493, createdName=雕雕, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1624970, encodeId=18b716249e015, content=<a href='/topic/show?id=0333412062' target=_blank style='color:#2F92EE;'>#Cas#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4120, encryptionId=0333412062, topicName=Cas)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=411420689333, createdName=yaanren, createdTime=Fri Feb 26 15:02:15 CST 2021, time=2021-02-26, status=1, ipAttribution=)]
    2021-02-26 yaanren

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英国MHRA允许开展阿霉素“前药”AVA6000治疗实体瘤的临床试验

AVA6000在进入肿瘤微环境之前一直处于循环失活状态,然后被成纤维细胞激活蛋白(FAP)所激活。FAP酶在大多数实体瘤中普遍存在,但在健康组织(例如心脏)中并不普遍。

Cell matabolism:向肥胖说不!Cell子刊揭示肥胖对乳腺癌恶化的作用机制

肌酸介导的脂肪细胞与癌细胞之间的交流可能会调节肥胖引起的乳腺癌。

Eur Radiol:乳腺钼靶之钙化灶——可疑形态钙化的临床意义在哪里?

乳腺钼靶摄片中经常发现多种形态可疑的钙化灶,这些钙化灶可用于检测乳腺癌的存在并预测其侵袭性。那钙化灶在乳腺癌的诊断权重有多大呢?