細胞間接着−核内受容体経路による新規細胞制御機構

杉本 幸太郎福島県立医大 基礎病理学講座

幹細胞

転写因子

上皮細胞

細胞接着はシグナルの起点となる

• 液性因子：ホルモン・サイトカイン・栄養・塩濃度など• 細胞接着：細胞が何とどの程度、接着しているか

液性因子細胞間接着細胞基質間接着

CLDN6シグナルはSFK/PI3K/AKTを介してレチノイン酸受容体をセリンリン酸化する

CLDN6PI3K

AKTSFKs

CLDN6

RARE

S379RXR RAR

Target geneDBD

AF1LBD

DBDAF1

LBD

P

268269371390

(L257)(D258)(S360)(S379)

KNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAQRRPRDRFLYAKLLGLLAELRSINEAYGYQIQHIQGLS-AMMPLLQEICSSQYPNQPSRFGKLLLRLPSLRTVSSSVIEQLFFVRLVGKTPIETLIRDMLSQYPNQPTRFGKLLLRLPSLRTVSSSVIEQLFFVRLVGKTPIETLIRDMLAQYPSQPQRFGRLLLRLPALRAVPASLISQLFFMRLVGKTPIETLIRDMLTLQ-QQHQRLAQLLLILSHIRHMSNKGMEHLYSMKCKNVVPLYDLLLEMLSSQ-QQSMRLANLLMLLSHVRHASNKGMEHLLNMKCKNVVPVYDLLLEMLPGGGAERRRAGRLLLTLPLLRQTAGKVLAHFYGVKLEGKVPMHKLFLEMLE----EPWRTGKLLLTLPLLRQTAAKAVQHFYSVKLQGKVPMHKLFLEMLE----DPRRAGKMLMTLPLLRQTSTKAVQHFYNIKLEGKVPMHKLFLEML--QPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLCEIWD-KYTHQPNRFPDLMMCLPEIRYIAGKMVNVPLEQLPLLFKVVLHSCKTSVNSS-QNWQRFYQLTKLLDSMHEVVENLLNYCFQTFLD-KTMSIEFPEMLADRQYDSRGRFGELLLLLPTLQSITWQMIEQIQFIKLFGMAKIDNLLQEMLDRQYDSRGRFGELLLLLPTLQSITWQMIEQIQFVKLFGMVKIDNLLQEMLCNYPQQTEKFGQLLLRLPEIRAISMQAEEYLYYKHLNGDVPYNNLLIEMLH--PHDRLMFPRMLMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDR--PQDQLRFPRMLMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDNSG-QSWQRFYQLTKLLDSMHDLVSDLLEFCFYTFRESHALKVEFPAMLVAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPIIDKIF--GQALEPTESKVLGALVELRKICTLGLQRIFYLKLEDLVSPPSIIDKLFNGGLNRPNYLSKLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPAIIDKLF

ARCARCOUPTFaCOUPTFbCOUPTFgERaERbERRaERRbERRgFXRGFNFGRHNF4aHNF4gLRH1LXRaLXRbMRNGF1BNOR1NURR1

●●●●●●●●●●●●●●●●●●●●●

AHHPSQPVRFGKLLLLLPSLRFITAERIELLFFRKTIGNTPMEKLLCDMFSNHPDDIFLFPKLLQKMADLRQLVTEHAQLVQIIKKTESDAALHPLLQEIANHPDAQYLFPKLLQKMADLRQLVTEHAQMMQRIKKTETETSLHPLLQEILNHPESSQLFAKLLQKMTDLRQIVTEHVQLLQVIKKTETDMSLHPLLQEIKGVVSSSQRFYQLTKLLDNLHDLVKQLHLYCLNTFIQSRALSVEFPEMMSRPQPAHRFLFLKIMAMLTELRSINAQHTQRLLRIQDIHPFATPLMQELFG--RPSRPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEML--RPSKPHMFPKILMKITDLRSISAKGAERVITLKMEIPGSMPPLIQEML--RPSQPYMFPRMLMKITDLRGISTKGAERAITLKMEIPGPMPPLIREMLKNRPLETSRFTKLLLKLPDLRTLNNMHSEKLLSFRVDAQ-----------KNHPNEASIFTKLLLKLPDLRSLNNMHSEELLAFKVHP------------KNHRED-GILTKLICKVSTLRALCGRHTEKLMAFKAIYPDIVRLHFPPLYKNHLDD-ETLAKLIAKIPTITAVCNLHGEKLQVFKQSHPEIVNTLFPPLYKTHR---QSILAKLPPKGKLRSLCSQHVERLQIFQHLHPIVVQAAFPPLYHKYPEQPGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLQKYPEQQGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLQKYPEQPGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLCHYPHCGDKFQQLLLCLVEVRALSMQAKEYLYHKHLGNEMPRNNLLIEMLTRYPTQPCRFGKLLLLLPALRSISPSTIEEVFFKKTIGNVPITRLLSDMYKTYPDDTYRLSRLLLRLPALRLMNATITEELFFKGLIGNIRIDSVIPHILKTYSEDTYRLARILVRLPALRLMSSNITEELFFTGLIGNVSIDSIIPYILHPPPGSHLLYAKMIQKLADLRSLNEEHSKQYRCLSFQPECSMKLTPLVLE

PNRPPARaPPARdPPARgPRPXRRARaRARbRARgREVERBaREVERBbRORaRORbRORgRXRaRXRbRXRgSF1TLXTR2TR4VDR

●●●●●●●●●●●●●●●●●●●●●●

●●●●●●●●●●●●●●●●●●●●●●

第379番セリンは14種のヒト核内受容体で保存されている

Kojima and Sugimoto et al., Cancers, 2020

CLDN6高発現は子宮体がんの予後不良因子HE CLDN6

Neg

ativ

eM

oder

ate

Wea

kSt

rong

log2 fold increase vs. wild type Ishikawa–4 +40

0.0

1.0

2.0

3.0

4.0

5.0

6.0

1 2 3 4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

1 2 3 4

0.0

1.0

2.0

3.0

4.0

5.0

1 2 3 4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

1 2 3 4

ESR1–/–CLDN6

Ishikawa

● ● ● ●● ● ● ●

AXLP

まとめ新経路の発見：CLDN6 → Src/PI3K/AKT → 核内受容体

1. CLDN6 → RAR： 幹細胞の上皮分化

2. CLDN6 → ERα： 子宮体がんの進展

3. CLDN4 → LXR： 乳がんの進展？

CLDN4PI3K

AKTSFKs

CLDN4

LXRE

RXR LXR

DBDAF1

LBD

P

増殖・浸潤・代謝？

Target genes

乳癌細胞

PI3K

AKTSFKs

CLDN6

ERE

ERα ERα

DBDAF1

LBD

P

増殖・浸潤

Target genes

子宮内膜癌細胞

CLDN6CLDN6PI3K

AKTSFKs

CLDN6

RARE

RXR RARs

DBDAF1

LBD

P

上皮分化

Target genes

幹細胞

Sugimoto et al., PLoS One, 2013; Sugimoto et al., PNAS, 2019;Kojima et al., Cancers, 2020; Kojima et al., in revision; Murakami et al., in preparation