更新于：2024-05-01

MAP3K2

mitogen-activated protein kinase kinase kinase 2

更新于：2024-05-01

基本信息

别名

MAP/ERK kinase kinase 2、MAP3K2、MAPK/ERK kinase kinase 2

+ [6]

简介

Component of a protein kinase signal transduction cascade. Regulates the JNK and ERK5 pathways by phosphorylating and activating MAP2K5 and MAP2K7 (By similarity). Plays a role in caveolae kiss-and-run dynamics.

关联

100 项与 MAP3K2 相关的临床结果

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100 项与 MAP3K2 相关的转化医学

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0 项与 MAP3K2 相关的专利（医药）

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1,255

项与 MAP3K2 相关的文献（医药）

2024-02-14·Signal transduction and targeted therapy

Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy.

Article

作者: Yan Guo ; Pan Xiang ; Xiaojiao Sun ; Wei Liu ; Jiafeng Zhou ; Bin Yin ; Lin Hou ; Boqin Qiang ; Huiliang Li ; Pengcheng Shu ; Xiaozhong Peng

The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits, and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways. Here, we identified that DOK6, a member of the Dok (downstream of tyrosine kinases) family, is required for the maintenance of peripheral axons, and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice, manifested as impaired sensory, abnormal posture, paw deformities, blocked nerve conduction, and dysmyelination. Furthermore, Dok6 is highly expressed in peripheral neurons but not in Schwann cells, and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding, axon destruction, and hindered retrograde axonal transport. Specifically, DOK6 acts as an adaptor protein for selectivity-mediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB. DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation, including MAP1B, Tau and Dynein for axonal transport, and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis. This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.

2023-11-15·Science advances

The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer.

Article

作者: Sabeen Ikram ; Apurv Rege ; Maraki Y Negesse ; Alexandre G Casanova ; Nicolas Reynoird ; Erin M Green

Aberrant activation of Ras/Raf/mitogen-activated protein kinase (MAPK) signaling is frequently linked to metastatic prostate cancer (PCa); therefore, the characterization of modulators of this pathway is critical for defining therapeutic vulnerabilities for metastatic PCa. The lysine methyltransferase SET and MYND domain 3 (SMYD3) methylates MAPK kinase kinase 2 (MAP3K2) in some cancers, causing enhanced activation of MAPK signaling. In PCa, SMYD3 is frequently overexpressed and associated with disease severity; however, its molecular function in promoting tumorigenesis has not been defined. We demonstrate that SMYD3 critically regulates tumor-associated phenotypes via its methyltransferase activity in PCa cells and mouse xenograft models. SMYD3-dependent methylation of MAP3K2 promotes epithelial-mesenchymal transition associated behaviors by altering the abundance of the intermediate filament vimentin. Furthermore, activation of the SMYD3-MAP3K2 signaling axis supports a positive feedback loop continually promoting high levels of SMYD3. Our data provide insight into signaling pathways involved in metastatic PCa and enhance understanding of mechanistic functions for SMYD3 to reveal potential therapeutic opportunities for PCa.

2023-11-02·American journal of physiology. Renal physiology

Vasopressin V2 Receptor, Tolvaptan, and ERK1/2 Phosphorylation in the Renal Collecting Duct.

Article

作者: Shaza Khan ; Viswanathan Raghuram ; Lihe Chen ; Chung-Lin Chou ; Chin-Rang Yang ; Syed J Khundmiri ; Mark A Knepper

Tolvaptan, a vasopressin antagonist selective for the V2-subtype vasopressin receptor (V2R), is widely used in the treatment of hyponatremia and autosomal-dominant polycystic kidney disease (ADPKD). Its effects on signaling in collecting duct cells have not been fully characterized. Here, we perform RNA-seq in a collecting duct cell line (mpkCCD). The data show that tolvaptan inhibits the expression of mRNAs that were previously shown to be increased in response to vasopressin including aquaporin-2, but also reveals mRNA changes that were not readily predictable and suggest off-target actions of tolvaptan. One such action is activation of the MAPK kinase (ERK1/ERK2) pathway. Prior studies have shown that ERK1/ERK2 activation is essential in the regulation of a variety of cellular and physiological processes and can be associated with cell proliferation. In immunoblotting experiments, we demonstrated that ERK1/ERK2 phosphorylation in mpkCCD cells was significantly reduced by vasopressin, in contrast to the increases seen in non-collecting-duct cells overexpressing V2R in prior studies. We also found that tolvaptan has a strong effect to increase ERK1/ERK2 phosphorylation in the presence of vasopressin and that tolvaptan's effect to increase ERK1/ERK2 phosphorylation is absent in mpkCCD cells in which both PKA-catalytic subunits have been deleted. Thus, it appears that the tolvaptan effect to increase ERK activation is PKA-dependent and is not due to an off-target effect of tolvaptan. We conclude that in cells expressing V2R at endogenous levels: 1) vasopressin decreases ERK1/ERK2 activation; 2) in the presence of vasopressin, tolvaptan increases ERK1/ERK2 activation; and 3) these effects are PKA-dependent.

项与 MAP3K2 相关的新闻（医药）

2022-06-21

·生物制品圈

免疫治疗新星：靶向HPK1的药物研发进展

造血祖细胞激酶1（Hematopoietic progenitor kinase 1 ，HPK1）是T细胞受体、B细胞受体和树突状细胞的负调节因子。HPK1激酶功能的丧失增加了细胞因子的分泌，增强了T细胞信号传导、病毒清除和肿瘤生长抑制。因此，HPK1被认为是肿瘤免疫治疗的一个有希望的靶点。据报道，几种HPK1抑制剂可调节T细胞功能。此外，还开发了能够诱导HPK1降解的HPK1靶向蛋白。最新一期JMC上，尤启冬等综述了HPK1的蛋白结构、功能和抑制剂的研究现状，并对HPK1靶向药物的未来发展提出了展望。HPK1是hematopoietic progenitor kinase 1（造血祖细胞激酶1）的简称，又名MAP4K1，是MAP4K家族的成员之一，它是一种丝/苏氨酸蛋白激酶。MAP4K家族中除HPK1外还有5个成员，包括MAP3K2、MAP4K3、MAP4K4、MAP4K5和MAP4K6。HPK1蛋白结构由N端激酶结构域（HPK1-KD）、四个富含脯氨酸（PR）的基序（PR1、PR2、PR3、PR4）和C端的柠檬酸同源结构域组成。PR1、PR2和PR4含有典型的II类结合基序，可与一系列含有Src同源3（SH3）结构域的衔接蛋白结合，如Grb2、Gads、Crk I/II、CrkL、Nck和HIP-55。这种结合模式不诱导磷酸化，表明HPK1蛋白的支架作用。HPK1的C端同源结构域可能作为调节结构域参与分子间相互作用。全长HPK1可在半胱氨酸蛋白酶切割位点（DDVD）被Caspas3切割，从而提高HPK1-KD的催化活性。HPK1激酶HPK1可与许多接头蛋白结合，如SLP76家族，Gads、HIP-55、GRB2家族，LAT、CRK家族等相互作用，活化造血干细胞的SAPK/JNK信号途径，从而对TCR通路进行负向调节。HPK1激酶是TCR信号的关键负反馈调节因子，能负调控树突细胞活化和T细胞与B细胞反馈；而抑制HPK1可增强T细胞活性，从而提高抗肿瘤免疫。HPK1主要由造血细胞包括其祖细胞表达。在T-细胞中，HPK1通过磷酰化SLP76上的Ser376和Gads上的Thr254激活SLP76，其磷酸化的复合体参与ERK信号途径的下调，并接到SLP-76的泛素化降解过程，导致TCR信号通路和T细胞增殖下降。2018年，Genentech的研究人员在Cell report上发表了一篇论文，显示共同阻断HPK1和PD-L1增强了抗肿瘤反应，证实HPK1可能提高检查点抑制剂功效。2020年8月28日，清华大学药学院廖学斌课题组与中山大学魏来课题组合作在《Cancer Cell》杂志上发表文章“造血祖细胞激酶1 (HPK1)通过有效调控T细胞功能，成为T细胞免疫治疗的药物靶点（Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies）”，该工作进一步证实HPK1可成为T细胞免疫疗法的药物热门研发靶点。HPK1抑制剂十多年前，研发人员就发现了HPK1可能是一种潜在的癌症免疫治疗靶点，但截止目前尚还没有相关药物上市。HPK1抑制剂开发所面临的挑战主要是HPK1 家族成员功能不同，设计高选择性抑制性化合物难度较大。据不完全统计，处于临床研发阶段的HPK1抑制剂包括：CFI-402411：是Treadwell Therapeutics公司研发的一种口服强效HPK1激酶抑制剂。临床前研究表明CFI-402411有望作为一种潜在的单一疗法，并与多种实体和血液癌症模型中的现有检查点抑制剂结合使用。2020年9月2日，该公司宣布CFI-402411的1/2期研究将进行首次患者给药，以评估TWT-101在实体瘤患者中作为单一疗法或与PD-1抑制剂联用的疗效。BGB-15025：是百济神州开发的一款高强度、高选择性的HPK1小分子口服抑制剂。2021年3月10日，百济神州公司宣布，一项针对其在研造血干细胞激酶1（HPK1）抑制剂BGB-15025的1期临床试验已完成首例患者给药。PRJ1-3024：是珠海宇繁研发的HPK1小分子抑制剂。PRJ1-3024胶囊分别于2021年11月和2022年2月在美国和中国进入临床试验阶段，主要用于胰腺癌、结直肠癌、肝癌等恶性肿瘤的免疫治疗。NDI-101150：无公开信息。其他研发中的小分子抑制剂结构包括下图（全部结构请阅读原文）等：已经报道的HPK1降解剂包括：在过去的5年中，已经报道了大量针对HPK1的小分子激酶抑制剂，大多数是ATP竞争性抑制剂。综合结构信息，作者发现与铰链相连的常见支架结构多为吲哚唑、氨基吡啶、氮杂吲哚等；面对P环的基团通常基于取代苯基或吡啶环；溶剂区域倾向于引入增溶基团如哌嗪或含氮杂环等。开发HPK1抑制剂的主要挑战是难以在MAP4K激酶家族中获得足够的选择性。此外，很难避免抑制参与TCR信号传导的其他相关激酶，如Src和其他Ste20样激酶家族。此外。已经报道了几种基于PROTAC技术的HPK1降解剂，这为靶向HPK1治疗创造了一个新的窗口，并可能进一步增强激酶的选择性。识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法小分子药物细胞疗法抗体蛋白降解靶向嵌合体