Cellular signalling最新文献_第7页

Regulatory role of Heparan sulfate in leptin signaling 硫酸肝素在瘦素信号传导中的调节作用。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111456

Naoko Nagai, Tatsumasa Shioiri, Sonoko Hatano, Nobuo Sugiura, Hideto Watanabe

Leptin, a hormone mainly secreted by adipocytes, has attracted significant attention since its discovery in 1994. Initially known for its role in appetite suppression and energy regulation, leptin is now recognized for its influence on various physiological processes, including immune response, bone formation, and reproduction. It exerts its effects by binding to receptors and initiating an intracellular signaling cascade. Heparan sulfate (HS) is known to regulate the intracellular signaling of various ligands. HS is present as the glycan portion of HSPGs on cell surfaces and in intercellular spaces, with diverse structures due to extensive sulfation and epimerization. Although HS chains on HSPGs are involved in many physiological processes, the detailed effects of HS chains on leptin signaling are not well understood.

This study examined the role of HS chains on HSPGs in leptin signaling using Neuro2A cells expressing the full-length leptin receptor (LepR). We showed that cell surface HS was essential for efficient leptin signaling. Enzymatic degradation of HS significantly reduced leptin-induced phosphorylation of downstream molecules, such as signal transducer and activator of transcription 3 and p44/p42 Mitogen-activated protein kinase. In addition, HS regulated LepR expression and internalization, as treatment with HS-degrading enzymes decreased cell surface LepR. HS was also found to exhibit a weak interaction with LepR. Enzymatic removal of HS enhanced the interaction between LepR and low-density lipoprotein receptor-related protein 1, suggesting that HS negatively regulates this interaction. In conclusion, HS plays a significant role in modulating LepR availability on the cell surface, thereby influencing leptin signaling. These findings provide new insights into the complex regulation of leptin signaling and highlight potential therapeutic targets for metabolic disorders and obesity.

瘦素是一种主要由脂肪细胞分泌的激素，自 1994 年被发现以来一直备受关注。瘦素最初因其在抑制食欲和能量调节方面的作用而为人所知，现在人们认识到它对免疫反应、骨骼形成和生殖等各种生理过程都有影响。瘦素通过与受体结合并启动细胞内信号级联来发挥其作用。众所周知，硫酸肝素（HS）可调节各种配体的细胞内信号传导。HS 作为 HSPGs 的聚糖部分存在于细胞表面和细胞间隙中，由于广泛的硫酸化和外嵌合作用，其结构多种多样。虽然HSPGs上的HS链参与了许多生理过程，但HS链对瘦素信号转导的具体影响还不十分清楚。本研究利用表达全长瘦素受体（LepR）的 Neuro2A 细胞研究了 HSPG 上的 HS 链在瘦素信号转导中的作用。我们的研究表明，细胞表面的HS对有效的瘦素信号转导至关重要。酶降解HS可显著减少瘦素诱导的下游分子磷酸化，如信号转导和激活转录3以及p44/p42丝裂原活化蛋白激酶。此外，HS 还能调节 LepR 的表达和内化，因为用 HS 降解酶处理后，细胞表面的 LepR 会减少。研究还发现，HS与LepR之间存在微弱的相互作用。酶法去除 HS 可增强 LepR 与低密度脂蛋白受体相关蛋白 1 之间的相互作用，这表明 HS 负向调节了这种相互作用。总之，HS在调节细胞表面LepR的可用性，从而影响瘦素信号转导方面起着重要作用。这些发现为了解瘦素信号转导的复杂调控提供了新的视角，并突出了代谢紊乱和肥胖症的潜在治疗靶点。

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引用次数: 0

Game-changing breakthroughs to redefine the landscape of the renin-angiotensin-aldosterone system in health and disease. 改变游戏规则的突破，重新定义肾素-血管紧张素-醛固酮系统在健康和疾病中的作用。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111459

Pitchai Balakumar, Gowraganahalli Jagadeesh

Novel perspectives on the role of the renin-angiotensin-aldosterone system (RAAS) offer a groundbreaking understanding of the system's role in health and illness. Our understanding of the role of the RAAS in several diseases, such as heart failure, hypertension, metabolic disorders, and chronic renal disease, has been broadened by recent studies. Specific variations in RAAS pathways can affect the course of disease and response to treatment, as shown by genetic and molecular research. The dynamic and fast-evolving nature of RAAS research described in this special issue might transform our approach to managing renal, neurological, and cardiovascular health, among other disease conditions, including cancer.

关于肾素-血管紧张素-醛固酮系统（RAAS）作用的新观点为我们提供了对该系统在健康和疾病中作用的突破性认识。最近的研究拓宽了我们对 RAAS 在多种疾病（如心力衰竭、高血压、代谢紊乱和慢性肾病）中作用的认识。遗传和分子研究表明，RAAS通路的特定变异会影响疾病的进程和对治疗的反应。本特刊所描述的 RAAS 研究的动态性和快速发展性可能会改变我们管理肾脏、神经和心血管健康以及包括癌症在内的其他疾病的方法。

引用次数: 0

Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation Rheb1 缺乏会导致线粒体功能障碍，并通过促进 Atp5f1c 乙酰化加速荚膜衰老。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111451

Qingmiao Lu , Xiao Hu , Qing Hou , Long Yu , Kai Cao , Dafa Ding , Yibing Lu , Chunsun Dai

Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.

荚膜细胞衰老可导致糖尿病肾病（DKD）中荚膜细胞的持续损伤和白蛋白尿，但其机制仍不清楚。本研究通过免疫组化染色证实了糖尿病肾病患者和小鼠荚膜细胞的荚膜衰老。荚膜细胞中的 Rheb1 基因敲除会加重糖尿病小鼠荚膜细胞的衰老和损伤，但在 Tsc1 基因缺失诱导荚膜细胞特异性 mTORC1 激活的小鼠中，Rheb1 基因敲除会减轻荚膜细胞损伤。在培养的荚膜细胞中，Rheb1 的敲除明显加速了荚膜细胞的衰老，这与 mTORC1 无关。从机制上讲，DKD 患者荚膜细胞中的 PDH 磷酸化与荚膜细胞衰老相关。Rheb1 缺乏会降低 ATP、线粒体膜电位和呼吸链复合物的部分成分，并增强 ROS 的产生和 PDH 磷酸化，这表明线粒体在体外和体内均存在功能障碍。此外，Rheb1 与 Atp5f1c 相互作用，并在高葡萄糖条件下调节其乙酰化。总之，Rheb1缺乏会导致线粒体功能障碍，并通过促进Atp5f1c乙酰化加速荚膜衰老，而这种方式与mTORC1无关，这为治疗DKD提供了实验依据。

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引用次数: 0

Inhibition of TREM-1 ameliorates angiotensin II-induced atrial fibrillation by attenuating macrophage infiltration and inflammation through the PI3K/AKT/FoxO3a signaling pathway 抑制 TREM-1 可通过 PI3K/AKT/FoxO3a 信号通路减轻巨噬细胞浸润和炎症，从而改善血管紧张素 II 诱导的心房颤动。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111458

Xin Chen , Liming Yu , Shan Meng , Jikai Zhao , Xinyi Huang , Zhishang Wang , Zijun Zhou , Yuting Huang , Tao Hong , Jinfeng Duan , Tong Su , Zijun Cao , Yanbang Chi , Tao Huang , Huishan Wang

Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.

炎症和免疫细胞浸润与心房颤动（房颤）的发病机制密切相关。髓系细胞上表达的触发受体-1（TREM-1）是一种炎症增强因子，与多种心血管疾病有关。然而，TREM-1在心房颤动发病过程中的确切作用和潜在机制仍不明确。研究人员使用房颤患者的心房样本来评估 TREM-1 的表达水平。建立了血管紧张素II（Ang II）诱导的房颤小鼠模型，以评估TREM-1的功能。通过超声心动图、程序化经静脉心脏起搏和心房电生理图评估心脏功能和房颤诱导性。使用流式细胞术评估了外周血和心房炎症细胞。通过组织学、大量 RNA 测序、生化分析和细胞培养，阐明了 TREM-1 在房颤中的机制作用。在心房颤动患者的心房中，TREM-1表达上调并与巨噬细胞共定位。药物抑制 TREM-1 可减少 Ang II 诱导的心房扩大和电重塑。抑制 TREM-1 还能改善 Ang II 诱导的 NLRP3 炎症小体激活、炎症因子释放、心房纤维化和巨噬细胞浸润。转录组分析表明，TREM-1 通过 PI3K/AKT/FoxO3a 信号通路调节 Ang II 诱导的炎症。体外研究进一步证实了这些发现，表明TREM-1的激活会加剧Ang II诱导的炎症，而过量表达FoxO3a则会抵消这种效应。这项研究发现了 TREM-1 在心房颤动发病机制中的关键作用及其潜在的分子机制。抑制 TREM-1 为治疗心房颤动提供了一种新的治疗策略。

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引用次数: 0

GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy GDF15通过保护性自噬增强胃癌的抗厌氧菌性和转移性

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-09 DOI: 10.1016/j.cellsig.2024.111457

Xinyu Gao, Zhongwei Zhang, Qinyi Li, Guokai Tai, ZhiDong Wang

Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.

远处转移是导致胃癌（GC）患者死亡的一个普遍原因。细胞脱离细胞外基质（ECM）会导致细胞死亡，而细胞抗原（anoikis）是肿瘤转移的屏障。肿瘤细胞要想在循环系统中存活并转移，就必须获得抗anoikis能力。鉴别导致 GC 耐 anoikis 的分子过程至关重要，因为这可能有助于发现新的治疗靶点并改善 GC 患者的长期生存。在这项研究中，我们采用定量蛋白质组学方法确定了生长分化因子15（GDF15）是GC耐药的关键因素。我们发现，GDF15能增强保护性自噬，从而促进GC细胞的耐厌氧菌性。此外，通过DNA牵引试验，我们发现活化转录因子2（ATF2）是GDF15表达的关键调节因子，是GDF15的转录激活因子。这些发现共同表明，ATF2 和 GDF15 具有巨大的潜力，可作为候选靶点开发治疗策略，以解决 GC 的转移问题。

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引用次数: 0

Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury 水蒸发蛋白：大脑缺血损伤治疗干预的前沿领域。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-05 DOI: 10.1016/j.cellsig.2024.111452

Ashi Mannan , Maneesh Mohan , Anshika Gulati , Sonia Dhiman , Thakur Gurjeet Singh

Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.

脑缺血损伤的特点是脑部血流量减少，仍然是全球发病率和死亡率的重要原因。尽管治疗方法有所改进，但仍迫切需要找到新的靶点来减轻缺血性中风的影响。水通道蛋白家族中的水蒸发蛋白最近被发现有望成为治疗脑缺血损伤的候选靶点。目前已确定的水通道蛋白有 13 种，其中 AQP4 与脑缺血有密切关系，因为有报道称，调节 AQP4 的活性可为治疗干预提供一种可能的途径，同时它们在 pH 值、渗透、离子和血脑屏障（BBB）中的作用也是脑缺血损伤的可能治疗靶点。这些分子通路可与特定的细胞通路相互作用，参与神经炎症，并可能与其他被认为与中风病因有关的蛋白质相互作用。了解这些通路为了解 AQPs 在脑缺血中的不同作用提供了重要信息，为开发重点/靶向疗法铺平了道路。

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引用次数: 0

Octreotide protects against LPS-induced endothelial cell and lung injury 奥曲肽可防止 LPS 诱导的内皮细胞和肺损伤。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-05 DOI: 10.1016/j.cellsig.2024.111455

Saikat Fakir, Khadeja-Tul Kubra, Nektarios Barabutis

Growth hormone (GH) is a crucial regulator of growth, cell reproduction, and regeneration; and it is controlled by growth hormone-releasing hormone (GHRH) and somatostatin. Lipopolysaccharides (LPS) can compromise endothelial function, leading to increased inflammation and vascular leak. Octreotide (OCT) is an FDA-approved synthetic somatostatin analog (SSA) used to treat acromegaly and neuroendocrine tumors. The present study investigates the effects of OCT on LPS-induced injury in bovine and human lung endothelial cells, as well as in mouse lungs. Our in vitro observations suggest that OCT effectively counteracts LPS-induced endothelial leak, inflammation, and reactive oxygen species (ROS) generation. Furthermore, OCT reduces bronchoalveolar lavage fluid (BALF) protein concentration in an experimental model of Acute Lung Injury (ALI). Our study suggests that OCT mitigates LPS-induced endothelial cell and lung injury, suggesting that it may represent an exciting therapeutic possibility in diseases related to barrier dysfunction.

生长激素（GH）是生长、细胞繁殖和再生的重要调节剂，受生长激素释放激素（GHRH）和体生长激素控制。脂多糖（LPS）会损害内皮功能，导致炎症和血管渗漏增加。奥曲肽 (OCT) 是一种经 FDA 批准的合成体生长抑素类似物 (SSA)，用于治疗肢端肥大症和神经内分泌肿瘤。本研究调查了 OCT 对牛和人肺内皮细胞以及小鼠肺内 LPS 诱导损伤的影响。我们的体外观察结果表明，OCT 能有效对抗 LPS 诱导的内皮渗漏、炎症和活性氧（ROS）生成。此外，OCT 还能降低急性肺损伤（ALI）实验模型中支气管肺泡灌洗液（BALF）的蛋白质浓度。我们的研究表明，OCT 可减轻 LPS 诱导的内皮细胞和肺损伤，这表明它可能是治疗与屏障功能障碍有关的疾病的一种令人兴奋的方法。

引用次数: 0

Retraction notice to “MicroRNA-148a-3p enhances the effects of sevoflurane on hepatocellular carcinoma cell progression via ROCK1 repression” [Cellular Signalling 83 (2021) 109982] 关于 "MicroRNA-148a-3p 通过抑制 ROCK1 增强七氟烷对肝癌细胞进展的影响 "的撤稿通知 [Cellular Signalling 83 (2021) 109982]。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-05 DOI: 10.1016/j.cellsig.2024.111436

Yan Sun , Li Liu , Wanying Xing , Hai Sun

引用次数: 0

Resveratrol inhibits white adipose deposition by the ESR1-mediated PI3K/AKT signaling pathway 白藜芦醇通过 ESR1 介导的 PI3K/AKT 信号通路抑制白色脂肪沉积。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-04 DOI: 10.1016/j.cellsig.2024.111448

Bao Yang , Qian Wang , Yin Li , Sanbao Zhang , Yanjie Sun , Yangyang Wei , Qinyang Jiang , Yanna Huang

Excessive adipose accumulation is the primary cause of obesity. Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its anti-obesity properties. However, the precise mechanisms by which RES influences fat deposition have not yet been explored. In this study, the aim was to identify the target proteins and associated pathways of RES in order to elucidate the mechanisms by which RES reduces fat deposition. In this study, mice were administered 400 mg/kg of RES via gavage for 12 weeks. We found that while 400 mg/kg RES had no impact on the growth of the mice, it significantly reduced the weight of various white adipose tissues, as well as the serum and liver concentrations of total cholesterol and triglycerides. Network pharmacology identified 15 potential targets of RES and highlighted the PI3K/AKT signaling pathway as a key pathway. Molecular docking and dynamic simulations suggested that ESR1 might be the target protein through which RES exerts its anti-fat deposition effects. In vitro experiments revealed that ESR1 promotes the proliferation and inhibits the differentiation of 3 T3-L1 adipocytes, and suppresses the PI3K/AKT signaling pathway. Silencing the ESR1 gene altered the ability of RES to inhibit cell differentiation via the PI3K/AKT pathway. Gene expression results in subcutaneous adipose tissue, epididymal fat tissue, and liver tissue of mice were consistent with observations in cells. In summary, RES reduces white fat deposition by directly targeting the ESR1 protein and inhibiting the PI3K/AKT signaling pathway. Our findings provide new insights into the potential use of RES in the prevention and treatment of obesity.

脂肪过度堆积是肥胖的主要原因。白藜芦醇（RES）是一种天然多酚化合物，因其抗肥胖特性而备受关注。然而，RES 影响脂肪沉积的确切机制尚未探明。本研究旨在确定 RES 的靶蛋白和相关途径，以阐明 RES 减少脂肪沉积的机制。在这项研究中，通过灌胃给小鼠服用每公斤 400 毫克的 RES，持续 12 周。我们发现，虽然每公斤 400 毫克的 RES 对小鼠的生长没有影响，但它能显著降低各种白色脂肪组织的重量，以及血清和肝脏中总胆固醇和甘油三酯的浓度。网络药理学确定了 RES 的 15 个潜在靶点，并强调 PI3K/AKT 信号通路是一个关键通路。分子对接和动态模拟表明，ESR1可能是RES发挥抗脂肪沉积作用的靶蛋白。体外实验发现，ESR1能促进3个T3-L1脂肪细胞的增殖和抑制分化，并抑制PI3K/AKT信号通路。沉默 ESR1 基因改变了 RES 通过 PI3K/AKT 途径抑制细胞分化的能力。小鼠皮下脂肪组织、附睾脂肪组织和肝组织中的基因表达结果与细胞中的观察结果一致。总之，RES通过直接靶向ESR1蛋白和抑制PI3K/AKT信号通路来减少白色脂肪沉积。我们的研究结果为RES在预防和治疗肥胖症方面的潜在应用提供了新的见解。

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引用次数: 0

The major vault protein integrates adhesion-driven signals to regulate collagen remodeling 主要拱顶蛋白整合了粘附驱动的信号，以调节胶原蛋白的重塑。

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2024-10-04 DOI: 10.1016/j.cellsig.2024.111447

Nuno M. Coelho , Pardis Riahi , Yongqiang Wang , Aiman Ali , Masoud Norouzi , Max Kotlyar , Igor Jurisica , Christopher A. McCulloch

DDR1 interacts with fibrillar collagen and can affect β1 integrin-dependent signaling, but the mechanism that mediates functional interactions between these two different receptors is not defined. We searched for molecules that link DDR1 and β1 integrin-dependent signaling in response to collagen binding. The activation of DDR1 by binding to fibrillar collagen reduced by 5-fold, β1 integrin-dependent ERK phosphorylation that leads to MMP1 expression. In contrast, pharmacological inhibition of DDR1 or culturing cells on fibronectin restored ERK phosphorylation and MMP1 expression mediated by the β1 integrin. A phospho-site screen indicated that collagen-induced DDR1 activation inhibited β1 integrin-dependent ERK signaling by regulating autophosphorylation of focal adhesion kinase (FAK). Immunoprecipitation, mass spectrometry, and protein-protein interaction mapping showed that while DDR1 and FAK do not interact directly, the major vault protein (MVP) binds DDR1 and FAK depending on the substrate. MVP associated with DDR1 in cells expressing β1 integrin that were cultured on collagen. Knockdown of MVP restored ERK activation and MMP1 expression in DDR1-expressing cells cultured on collagen. Immunostaining of invasive cancers in human colon showed colocalization of DDR1 with MVP. These data indicate that MVP interactions with DDR1 and FAK contribute to the regulation of β1 integrin-dependent signaling pathways that drive collagen degradation.

DDR1 与纤维胶原相互作用，可影响β1整合素依赖性信号传导，但这两种不同受体之间功能性相互作用的介导机制尚未明确。我们寻找了连接 DDR1 和 b1 整合素依赖性信号转导与胶原蛋白结合的分子。与纤维胶原结合激活 DDR1 后，b1 整合素依赖的 ERK 磷酸化减少了 5 倍，而 ERK 磷酸化会导致 MMP1 的表达。相反，药物抑制 DDR1 或在纤维粘连蛋白上培养细胞可恢复 b1 整合素介导的 ERK 磷酸化和 MMP1 表达。磷酸化位点筛选表明，胶原诱导的 DDR1 激活通过调节焦点粘附激酶（FAK）的自身磷酸化，抑制了 β1 整合素依赖的 ERK 信号转导。免疫沉淀、质谱分析和蛋白质相互作用图谱显示，虽然DDR1和FAK不直接相互作用，但主要拱顶蛋白（MVP）会根据底物的不同与DDR1和FAK结合。在胶原蛋白上培养的表达 b1 整合素的细胞中，MVP 与 DDR1 相关。在胶原上培养的表达 DDR1 的细胞中，敲除 MVP 可恢复 ERK 的激活和 MMP1 的表达。人结肠浸润性癌症的免疫染色显示 DDR1 与 MVP 共定位。这些数据表明，MVP 与 DDR1 和 FAK 的相互作用有助于调节驱动胶原降解的 β1 整合素依赖性信号通路。

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引用次数: 0