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TGF-β signaling and regulation: Elucidating molecular mechanisms and pathogenic functions of the ‘co-receptor’ Cripto-1 and the receptor BMPRII

TGF-β 信号传导和调节：阐明辅助受体 Cripto-1 和受体 BMPRII 的分子机制和致病功能

基本信息

批准号：
10365923
负责人：
Erik Matthias Martinez Hackert
金额：
$ 30.5万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY TGF-β family proteins are critically important for human health. They regulate differentiation, proliferation and homeostasis in normal cell physiology, but mutations or abnormal expression are associated with devastating diseases, including cancers, and Pulmonary Arterial Hypertension (PAH). Discovering therapeutics that target TGF-β family proteins is an urgent priority and will have a great impact on human health. However, identifying therapeutics has been difficult, because the physiological and pathological activities of TGF-β family proteins are poorly defined. A profound molecular understanding of TGF-β family action is essential to overcome these obstacles. Thus, the overarching goal of the lab is to determine how TGF-β family signaling is regulated and to link our findings with physiological and pathological processes. We blend tools of structural biology, biochemistry and cell biology. Here, we have two aims. In Aim 1 we will validate the newly established mechanism of ligand recognition by Cripto-1 family co-receptors and examine the roles of membrane-anchored and soluble Cripto-1 in cancers. Cripto-1 is a membrane-anchored, EGF-CFC family `co-receptor' that promotes tumor progression. It can both potentiate and inhibit TGF-β family signaling. But how Cripto-1 mediates these opposing activities is not clear. Our recent studies suggest a mechanism. Cripto-1 blocks binding of TGF-β family ligands to receptors. Thus, a soluble form inhibited signaling. But membrane-anchored Cripto-1 potentiated signaling and promoted tumorigenesis. We hypothesize that membrane-anchored Cripto-1 captures ligands at the cell surface and directs ligands into endosomes for signal potentiation and oncogenic activation. Elucidating the Cripto-1/EGF-CFC mechanism of ligand capture and oncogenic activation could reveal epitopes and modalities to target Cripto-1 in cancers. In Aim 2 we will identify the ligand binding determinants of the `type II' TGF-β family receptor BMPRII and establish functional consequences of ligand binding-competition for BMPRII mediated signaling and PAH. TGF-β family signals are transduced via SMAD transcription factors. In PAH, BMPRII mediated SMAD1/5/8 signaling is reduced. Just how is not understood. Our recent findings offer a clue. We discovered that ligands regulated by Cripto-1 or its homolog Cryptic bind BMPRII with high affinity. Until now, BMPRII was believed to be a low affinity receptor for BMPs, a subclass of TGF-β family ligands. We also found that high affinity ligands inhibit BMP dependent SMAD1/5/8 signaling by competing for receptor binding. We hypothesize that Cripto-1/Cryptic ligands suppress BMPRII mediated SMAD1/5/8 signaling in PAH by competing with BMPs for BMPRII binding. Demonstrating that binding- competition promotes PAH phenotypes and identifying epitopes on ligands that contact BMPRII could lead to development of inhibitors that prevent high affinity BMPRII ligands from competing with low affinity BMPs, and thus could help restore BMPRII mediated SMAD1/5/8 signaling in PAH. Successful completion of these studies could help open new avenues for targeting Cripto-1 in cancers and for restoring BMPRII function in PAH.

项目摘要 TGF-β家族蛋白对人类健康至关重要。它们调节分化、增殖和在正常细胞生理学中的稳态，但突变或异常表达与破坏性的疾病，包括癌症和肺动脉高压（PAH）。发现靶向 TGF-β家族蛋白质是一个迫切的优先事项，并将对人类健康产生重大影响。然而，识别由于TGF-β家族蛋白质的生理和病理活性，定义不明确。对TGF-β家族作用的深刻分子理解对于克服这些障碍至关重要。障碍.因此，该实验室的首要目标是确定TGF-β家族信号转导是如何调节的，将我们的发现与生理和病理过程联系起来。我们混合了结构生物学的工具，生物化学和细胞生物学在这里，我们有两个目标。在目标1中，我们将验证新建立的 Cripto-1家族共受体的配体识别机制，并检查膜锚定蛋白的作用。和可溶性Cripto-1在癌症中的作用。Cripto-1是一种膜锚定的EGF-CFC家族“共受体”，促进肿瘤进展。它可以增强和抑制TGF-β家族信号传导。但是克里普托-1 调解这些对立的活动是不清楚的。我们最近的研究提出了一种机制。Cripto-1块 TGF-β家族配体与受体的结合。因此，可溶形式抑制信号传导。但膜锚定 Cripto-1增强信号传导并促进肿瘤发生。我们假设膜锚定的Cripto-1 捕获细胞表面的配体并将配体引导到核内体中以增强信号并致癌 activation.阐明Cripto-1/EGF-CFC的配体捕获和致癌激活机制，揭示了在癌症中靶向Cripto-1的表位和模式。在目标2中，我们将确定配体结合 “II型”TGF-β家族受体BMPRII的决定簇，并建立配体的功能后果 BMPRII介导的信号传导和PAH的结合竞争。TGF-β家族信号通过SMAD转导转录因子在PAH中，BMPRII介导的SMAD 1/5/8信号传导减少。只是如何不被理解。我们最近的发现提供了一个线索。我们发现受Cripto-1或其同源物Cryptic调控的配体与具有高亲和力的BMPRII。到目前为止，BMPRII被认为是BMP的低亲和力受体，BMP是BMPs的亚类。 TGF-β家族配体。我们还发现，高亲和力配体通过以下方式抑制BMP依赖性SMAD 1/5/8信号传导：竞争受体结合。我们假设Cripto-1/隐藏蛋白配体抑制BMPRII介导的 SMAD 1/5/8信号通过与BMPs竞争BMPRII结合在PAH中。证明这种约束力- 竞争促进PAH表型，并识别与BMPRII接触的配体上的表位，开发防止高亲和力BMPRII配体与低亲和力BMP竞争的抑制剂，和因此可以帮助恢复PAH中BMPRII介导的SMAD 1/5/8信号传导。成功完成这些研究这可能有助于为靶向癌症中的Cripto-1和恢复PAH中的BMPRII功能开辟新的途径。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Type II BMP and activin receptors BMPR2 and ACVR2A share a conserved mode of growth factor recognition.

DOI：
10.1016/j.jbc.2022.102076
发表时间：
2022-07
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Chu, Kit-Yee;Malik, Anjali;Thamilselvan, Vijayalakshmi;Martinez-Hackert, Erik
通讯作者：
Martinez-Hackert, Erik

Smad2/3 Activation Regulates Smad1/5/8 Signaling via a Negative Feedback Loop to Inhibit 3T3-L1 Adipogenesis.