LRP6 mediates Wnt/β-catenin signaling and regulates adipogenic differentiation in human mesenchymal stem cells
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WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a β-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. β-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with β-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/β-catenin signaling, particularly in human cancer.
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The Wnt/β-catenin pathway controls cell proliferation, death and differentiation. Several families of extracellular proteins can antagonize Wnt/β-catenin signaling, including the decoy receptors known as secreted frizzled related proteins (SFRPs), which have a cysteine-rich domain (CRD) structurally similar to the extracellular Wnt-binding domain of the frizzled receptors. SFRPs inhibit Wnt signaling by sequestering Wnts through the CRD or by forming inactive complexes with the frizzled receptors. Other endogenous molecules carrying frizzled CRDs inhibit Wnt signaling, such as V3Nter, which is proteolytically derived from the cell surface component collagen XVIII and contains a biologically active frizzled domain (FZC18) inhibiting in vivo cell proliferation and tumor growth in mice. We recently showed that FZC18 expressing cells deliver short-range signals to neighboring cells, decreasing their proliferation in vitro and in vivo through the Wnt/β-catenin signaling pathway. Here, using low concentrations of soluble FZC18 and Wnt3a, we show that they physically interact in a cell-free system. In addition, soluble FZC18 binds the frizzled 1 and 8 receptors' CRDs, reducing cell sensitivity to Wnt3a. Conversely, inhibition of Wnt/β-catenin signaling was partially rescued by the expression of full-length frizzled 1 and 8 receptors, but enhanced by the expression of a chimeric cell-membrane-tethered frizzled 8 CRD. Moreover, soluble, partially purified recombinant FZC18_CRD inhibited Wnt3a-induced β-catenin activation. Taken together, the data indicate that collagen XVIII-derived frizzled CRD shifts Wnt sensitivity of normal cells to a lower pitch and controls their growth.
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Abstract The Wnt-signaling pathway plays a critical role in directing cell fate during embryogenesis. Several lines of evidence also suggest a role in inflammatory processes. Here, we analyzed whether Wnt signaling plays a role in leukocyte inflammatory responses. Monocytes from healthy donors expressed different Frizzled receptors, which are ligands for the Wnt molecules. Activation of the Wnt/β-catenin pathway by LiCl or Wnt3a increased β-catenin protein levels in monocytes but not in granulocytes. It is interesting that the activation of Wnt/β-catenin signaling via Wnt3a in monocytes resulted in a decrease in migration through an endothelial layer (human dermal microvascular endothelial cell-1). Further experiments revealed that the decrease in transendothelial migration was associated with specific monocyte adherence to endothelial cells after Wnt exposure. The specificity was verified by a lack of Wnt3a-induced adhesion to fibronectin, laminin, or collagen compared with endothelial interaction. Analysis of the distribution of β-catenin revealed a Wnt3a-induced increase of β-catenin in the cytoplasm. Wnt3a exposure did not result in any activation of the classical Wnt-target gene c-myc or a Wnt-target gene involved in cell adhesion (Connexin43). Our study implicates for the first time a role of canonical Wnt signaling in inflammatory processes in monocytes.
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407 Wnt 단백질은 Drosophila 유전자인 wingless와 생쥐 유 전자인 int-1의 합성어로서, 배아 및 성인에서 세포 증식, 분 화, 사멸 등과 같은 필수적인 생물학적 과정에 관여하는 성 장 인자이다[1~3]. 이러한 Wnt 경로의 배아 세포 돌연변이 는 여러가지 유전성 질환을 초래하고 체세포 돌연변이는 장 (intestine)을 비롯한 여러 가지 조직에서 종양을 일으킨다[4]. Wnt의 신호전달 체계는 현재 약 4가지 정도로 알려져 있 다[2]. 그 중 가장 많이 알려진 부분이 Wnt/β-catenin 신호전 달 경로이다. Frizzled는 Wnt의 seven-transmembrane 도메 인 수용체이며 저밀도지단백 수용체-관련 단백질-5/6 (low-density lipoprotein receptor-related proteins-5/6, LRP5/6)는 single-transmembrane 단백질로서 co-receptor로 작용한다. Wnt가 Lrp5/6 (in vertebrates) 또는 Arrow (in Drosophila) 및 Frizzled 단백질과 결합하면 세포 내 단백질 인 Dishevelled (Dsh)가 활성화되고 glycogen synthase kinase-3β (GSK-3β)가 억제되며 β-catenin으로부터 Axin이 유리되어 LRP5/6의 세포질 내 미부(cytoplasmic tail)와 결 합하게 된다. 신호가 없는 상황에서는 Axin은 scaffolding 단백질로서 adenomatous polyposis coli (APC) 및 GSK-3β 와 결합하여 세포 내의 β-catenin 분해 복합체(β-catenin degradation complex)를 형성하고, GSK-3β는 β-catenin을 인산화시켜 26S proteosome에 의해 β-catenin이 파괴된다. 그러나 Wnt가 결합하여 Axin이 Lrp5/6와 결합하고, GSK-3β 가 억제되면 β-catenin 분해 복합체가 해체되고 세포질 내에 β-catenin이 축적되어 핵 내로 들어가 T-cell factor/lymphoidenhancer binding factor (TCF/LEF)와 결합하여 표적 유전 자를 발현시키게 된다. 이와 같이 Wnt와 β-catenin이 관여하는 canonical Wntsignaling 경로가 골조직에서 골세포의 분화, 증식, 사멸 및 골량의 조절에 매우 중요한 역할을 하고 기계적인 부하에 대해 뼈가 반응하는 데에도 필요한 것으로 밝혀지고 있어, Wnt/β-catenin 신호전달 경로는 최근 수년간 골을 연구하는 분야에서 가장 주목받는 영역중 하나가 되었다. 그 외에 non-canonical planar cell polarity (PCP) 경로, Wnt/Ca 경 로 및 cAMP response element binding protein (CREB)이 관여하는 protein kinase A 경로 등이 있으며 골 및 골세포 기능에 있어서 이러한 경로들의 역할은 아직 잘 알려져 있 지 않고, 여러가지 Wnt 단백질들의 종류에 따라서 활성화되 는 경로가 다른 것으로 알려져 있다. 여러가지 세포외 단백 질들이 Wnt/β-catenin 신호전달 경로의 활성을 조절하는데, 이러한 단백질들은 Lrp5/6, Frizzled 또는 Wnt 단백질들과 상호작용한다. Wnt와 Frizzled 수용체 간의 결합은 secreted frizzled-related protein (sFRP) 및 Wnt inhibitory factor 1 (WIF-1)에 의해 억제되고, LRP5/6 coreceptor는 Dickkopf 1 (Dkk1)과 SOST 유전자 산물인 sclerostin에 의해 억제된 다. Wnt/β-catenin 신호 전달 경로에 의해 골형성이 증가하는 하나의 예로 조골세포의 발달 자극을 들 수 있는데, Lithium chloride (LiCl)는 GSK-3β를 억제하여 간엽전구세포가 조골 세포로 분화하도록 자극하고[5], 4주간 LiCl를 투여한 C57BL/6 생쥐에서는 조골세포의 수 및 골형성의 급격한 증 가를 보인다[6]. LiCl가 β-catenin을 안정화시키고 TCF 관련 유전자 활성을 증가시키며 Wnt 반응 유전자들의 발현을 증 가시키는 것은 이러한 것들이 Wnt/β-catenin 신호전달 경로 에 의한 것임을 시사한다[6]. 골조직에서 Wnt/β-catenin 신호전달 경로의 중요성은 LRP5의 돌연변이와 관련된 유전적 골질환이 발견되면서 보 다 확실해졌는데, 정상인에 비해 매우 높은 골밀도를 갖는 가계에서 linkage analysis를 통해 염색체 11q12-13에 high bone mass (HBM) 유전자가 존재하는 것이 확인되었고[7], 이것이 LRP5의 돌연변이에 의한 것임이 밝혀졌으며[8], G171V 돌연변이를 가진 환자에서 돌연변이가 일어난 LRP5 는 dkk-1과의 결합이 감소되어 Wnt/β-catenin 신호전달 경로 가 증가되어 있다[9]. 한편, LRP5의 기능 소실 돌연변이에 Wnt/β-catenin 신호 전달 체계를 통한 부갑상선호르몬의 골형성 촉진 효과
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Wnt-beta-catenin signaling controls critical events in metazoan development, and its dysregulation leads to cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane co-receptors Frizzled (Fz) and low-density lipoprotein (LDL) receptor-related protein (LRP) 5 or LRP6 inhibits the degradation of the transcriptional coactivator beta-catenin, which translocates to the nucleus to regulate gene expression. The secreted protein Dickkopf1 (Dkk1) inhibits Wnt signaling by binding to LRP5 and LRP6 and blocking their interaction with Wnt and Fz. Kremen 1 and 2 (Krm1 and 2, collectively termed Krms) are single-pass transmembrane Dkk1 receptors that synergize with Dkk1 to inhibit Wnt signaling by promoting the endocytosis of LRP5 and LRP6. A study now suggests that Krms, in the absence of Dkk1, potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane. It is proposed that the absence or presence of Dkk1 determines whether Krms will activate or inhibit Wnt-beta-catenin signaling, respectively. Here, we speculate that the proposed context-dependent positive and negative roles for Krms could promote biphasic Wnt signaling in response to a shallow gradient of Dkk1, resulting in the generation of precise and robust borders between cells during development. Identification of a context-dependent role for Krms in Wnt-beta-catenin signaling offers insight into the mechanism of Wnt signaling and has important developmental implications.
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