LRP6

LRP6
PDBに登録されている構造
PDB	オルソログ検索: RCSB PDBe PDBj
PDBのIDコード一覧
	3S2K, 3S8V, 3S8Z, 3S94, 3SOB, 3SOQ, 3SOV, 4A0P, 4DG6, 4NM5, 4NM7
識別子
記号	LRP6, ADCAD2, STHAG7, LDL receptor related protein 6
外部ID	OMIM: 603507 MGI: 1298218 HomoloGene: 1747 GeneCards: LRP6
遺伝子の位置 (ヒト)
染色体	12番染色体 (ヒト)
終点	12,267,044 bp
遺伝子の位置 (マウス)
染色体	6番染色体 (マウス)
終点	134,543,928 bp
RNA発現パターン
	; ;
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• low-density lipoprotein particle receptor activity; • apolipoprotein binding; • protein homodimerization activity; • kinase inhibitor activity; • frizzled binding; • Wnt-protein binding; • toxin transmembrane transporter activity; • 血漿タンパク結合; • coreceptor activity involved in Wnt signaling pathway; • identical protein binding; • Wnt-activated receptor activity; • 受容体結合; • coreceptor activity involved in canonical Wnt signaling pathway;
細胞の構成要素	• integral component of membrane; • Wnt-Frizzled-LRP5/6 complex; • Wnt signalosome; • ゴルジ体; • early endosome membrane; • 膜; • receptor complex; • シナプス; • 細胞外領域; • cell surface; • soma; • early endosome; • 小胞体; • カベオラ; • cytoplasmic vesicle; • 細胞膜; • 脂質ラフト;
生物学的プロセス	• negative regulation of protein phosphorylation; • Wnt signaling pathway involved in somitogenesis; • cerebellum morphogenesis; • roof of mouth development; • dopaminergic neuron differentiation; • positive regulation of Wnt signaling pathway involved in dorsal/ventral axis specification; • regulation of transcription, DNA-templated; • エンドサイトーシス; • receptor-mediated endocytosis involved in cholesterol transport; • embryonic pattern specification; • 収斂伸長運動; • negative regulation of protein kinase activity; • 視床発生; • axis elongation involved in somitogenesis; • canonical Wnt signaling pathway involved in neural crest cell differentiation; • positive regulation of cytosolic calcium ion concentration; • response to peptide hormone; • canonical Wnt signaling pathway involved in regulation of cell proliferation; • neural crest cell differentiation; • positive regulation of DNA-binding transcription factor activity; • Wntシグナル経路; • cellular response to cholesterol; • neural crest formation; • trachea cartilage morphogenesis; • positive regulation of transcription, DNA-templated; • odontogenesis of dentin-containing tooth; • 多細胞個体の発生; • midbrain-hindbrain boundary development; • neural tube closure; • positive regulation of cell cycle; • external genitalia morphogenesis; • Wnt signaling pathway involved in dorsal/ventral axis specification; • pericardium morphogenesis; • 大脳皮質発生; • embryonic retina morphogenesis in camera-type eye; • canonical Wnt signaling pathway; • negative regulation of protein serine/threonine kinase activity; • protein localization to plasma membrane; • negative regulation of canonical Wnt signaling pathway; • negative regulation of smooth muscle cell apoptotic process; • face morphogenesis; • primitive streak formation; • positive regulation of transcription by RNA polymerase II; • 化学的シナプス伝達; • toxin transport; • Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation; • positive regulation of canonical Wnt signaling pathway; • beta-catenin destruction complex disassembly; • midbrain dopaminergic neuron differentiation; • gastrulation with mouth forming second; • anterior/posterior pattern specification; • embryonic limb morphogenesis; • 中脳発生; • 骨再形成; • embryonic camera-type eye morphogenesis; • bone morphogenesis; • branching involved in mammary gland duct morphogenesis; • cell-cell adhesion;
	出典:Amigo / QuickGO
オルソログ
	4040
	16974
	ENSG00000070018; ENSG00000281324
	ENSMUSG00000030201
	O75581
	O88572
	NM_002336
	NM_008514
	NP_002327
	NP_032540
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

LRP6（low-density lipoprotein receptor-related protein 6）は、ヒトではLRP6遺伝子にコードされるタンパク質である^[5]^[6]。LRP6は古典的Wnt経路に関与するLRP5/LRP6/Frizzled受容体群の重要な構成要素である。

構造

LRP6は膜貫通型LDL（英語版）受容体タンパク質であり、LRP5と同様の構造を持つ。これらのタンパク質は全長約1600アミノ酸のうち、約85%が細胞外に位置する。N末端には4つのβプロペラモチーフと4つのEGF様リピートが交互に並んでいる。LRP5やLRP6に結合する細胞外リガンドの大部分はβプロペラ部分に結合する。22アミノ酸からなる領域が細胞膜を横断する1回膜貫通タンパク質であり、207アミノ酸からなる領域が細胞内に位置する^[7]。

機能

LRP6はLRP5やFrizzledタンパク質ファミリーのメンバーと共に補助受容体として機能し、古典的Wnt経路を介してWntタンパク質によるシグナルを伝達する^[7]。

相互作用

古典的Wntシグナルは、Frizzled受容体とLRP5/6補助受容体を介して、GSK3BのSer9のリン酸化に依存しない活性をダウンレギュレーションする^[8]。LRP5やLRP6の欠乏による古典的Wntシグナルの低下は、p120-カテニン（英語版）の分解を引き起こす^[9]。

LRP6はDickkopf（Dkk）ファミリーのタンパク質（DKK1（英語版）など^[10]）、スクレロスチン（英語版）、R-spondin、システインノット型タンパク質ファミリーのメンバーなどの細胞外タンパク質によって調節される^[7]。

臨床的意義

ヒトでは、LRP6の機能喪失変異は血漿中のLDLやトリグリセリドの増加、高血圧、糖尿病、骨粗鬆症を引き起こす^[7]。同様に、Lrp6に機能喪失変異を有するマウスも骨量が低下する^[11]。LRP6は副甲状腺ホルモン（PTH）治療に対する骨の同化応答に重要であり、LRP5はこの作用には関与していない^[11]。一方、LRP5が重要な役割を果たしているメカノトランスダクション（英語版）（力に対する骨の応答）には、LRP6は活性を持たないようである^[11]。LRP5の阻害因子の1つであるスクレロスチンは、骨細胞特異的なWntアンタゴニストとして、骨粗鬆症の臨床試験において有望な結果が得られている^[12]^[13]。

出典

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000070018、ENSG00000281324 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000030201 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ “Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family”. Biochem. Biophys. Res. Commun. 248 (3): 879–88. (1998). doi:10.1006/bbrc.1998.9061. PMID 9704021.
^ “Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6”. 2022年6月18日閲覧。
^ ^a ^b ^c ^d “Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone”. J. Bone Miner. Res. 24 (2): 171–8. (2009). doi:10.1359/jbmr.081235. PMC 3276354. PMID 19072724.
^ “Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades”. Cancer Biol. Ther. 5 (9): 1059–64. (2006). doi:10.4161/cbt.5.9.3151. PMID 16940750.
^ “Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members”. J. Cell Sci. 123 (Pt 24): 4351–65. (2010). doi:10.1242/jcs.067199. PMC 2995616. PMID 21098636.
^ “Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6”. Curr. Biol. 11 (12): 951–61. (2001). doi:10.1016/s0960-9822(01)00290-1. PMID 11448771.
^ ^a ^b ^c “New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction”. Front Endocrinol (Lausanne) 5: 246. (2014). doi:10.3389/fendo.2014.00246. PMC 4299511. PMID 25653639.
^ “WNT signaling in bone homeostasis and disease: from human mutations to treatments”. Nature Medicine 19 (2): 179–192. (February 2013). doi:10.1038/nm.3074. PMID 23389618.
^ “Regulation of Wnt/beta-catenin signaling within and from osteocytes”. Bone 54 (2): 244–249. (June 2013). doi:10.1016/j.bone.2013.02.022. PMC 3652284. PMID 23470835.

関連文献

“LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.”. Development 131 (8): 1663–77. (2004). doi:10.1242/dev.01117. PMID 15084453.
“Generation and analysis of 280,000 human expressed sequence tags.”. Genome Res. 6 (9): 807–28. (1997). doi:10.1101/gr.6.9.807. PMID 8889549.
“A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p).”. Genomics 56 (1): 40–50. (1999). doi:10.1006/geno.1998.5685. PMID 10036184.
“LDL-receptor-related proteins in Wnt signal transduction.”. Nature 407 (6803): 530–5. (2000). Bibcode: 2000Natur.407..530T. doi:10.1038/35035117. PMID 11029007.
“LDL-receptor-related protein 6 is a receptor for Dickkopf proteins.”. Nature 411 (6835): 321–5. (2001). Bibcode: 2001Natur.411..321M. doi:10.1038/35077108. PMID 11357136.
“Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6.”. Curr. Biol. 11 (12): 951–61. (2001). doi:10.1016/S0960-9822(01)00290-1. PMID 11448771.
“Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled.”. J. Biol. Chem. 277 (8): 5977–81. (2002). doi:10.1074/jbc.M111131200. PMID 11742004.
“Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. (2003). doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
“Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins.”. J. Biol. Chem. 278 (39): 37024–31. (2003). doi:10.1074/jbc.M300191200. PMID 12857724.
“A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor.”. Mol. Cell. Biol. 23 (16): 5825–35. (2003). doi:10.1128/MCB.23.16.5825-5835.2003. PMC 166321. PMID 12897152.
“The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway.”. J. Biol. Chem. 279 (17): 17535–42. (2004). doi:10.1074/jbc.M311292200. PMID 14739301.
“LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells.”. Am. J. Physiol. Heart Circ. Physiol. 287 (6): H2376–83. (2005). doi:10.1152/ajpheart.01173.2003. PMID 15271658.
“Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.”. Genome Res. 14 (9): 1711–8. (2004). doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
“The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”. Genome Res. 14 (10B): 2121–7. (2004). doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
“LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution.”. Oncogene 23 (56): 9129–35. (2005). doi:10.1038/sj.onc.1208123. PMID 15516984.
“SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.”. J. Biol. Chem. 280 (29): 26770–5. (2005). doi:10.1074/jbc.M504308200. PMID 15908424.
“Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding.”. J. Cell Sci. 118 (Pt 22): 5305–14. (2006). doi:10.1242/jcs.02651. PMID 16263759.
“The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity.”. J. Biol. Chem. 281 (8): 4787–94. (2006). doi:10.1074/jbc.M508657200. PMID 16365045.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000070018、ENSG00000281324 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000030201 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[pmid9704021-5] “Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family”. Biochem. Biophys. Res. Commun. 248 (3): 879–88. (1998). doi:10.1006/bbrc.1998.9061. PMID 9704021.

[entrez-6] “Entrez Gene: LRP6 low density lipoprotein receptor-related protein 6”. 2022年6月18日閲覧。

[Williams-7] “Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone”. J. Bone Miner. Res. 24 (2): 171–8. (2009). doi:10.1359/jbmr.081235. PMC 3276354. PMID 19072724.

[pmid16940750-8] “Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades”. Cancer Biol. Ther. 5 (9): 1059–64. (2006). doi:10.4161/cbt.5.9.3151. PMID 16940750.

[Hong-9] “Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members”. J. Cell Sci. 123 (Pt 24): 4351–65. (2010). doi:10.1242/jcs.067199. PMC 2995616. PMID 21098636.

[Semenov-10] “Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6”. Curr. Biol. 11 (12): 951–61. (2001). doi:10.1016/s0960-9822(01)00290-1. PMID 11448771.

[Kang-11] “New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction”. Front Endocrinol (Lausanne) 5: 246. (2014). doi:10.3389/fendo.2014.00246. PMC 4299511. PMID 25653639.

[Baron-12] “WNT signaling in bone homeostasis and disease: from human mutations to treatments”. Nature Medicine 19 (2): 179–192. (February 2013). doi:10.1038/nm.3074. PMID 23389618.

[:0-13] “Regulation of Wnt/beta-catenin signaling within and from osteocytes”. Bone 54 (2): 244–249. (June 2013). doi:10.1016/j.bone.2013.02.022. PMC 3652284. PMID 23470835.

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