Role of PI 3-Kinase Isoforms in Insulin Action

PI 3-激酶亚型在胰岛素作用中的作用

• 批准号: 9920716
• 负责人: C RONALD KAHN
• 金额: $ 44.13万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920716
• 关键词: 1-Phosphatidylinositol 3-Kinase; Catalytic Domain; Cell Nucleus; Cells; Complex; Development; Diabetes Mellitus; Disease; Dominant-Negative Mutation; Enzymes; Event; Genetic Transcription; Goals; Grant; Growth Factor; Homeostasis; In Vitro; Insulin; Insulin Resistance; Insulin Signaling Pathway; JNK-activating protein kinase; Knock-in Mouse; Knock-out; Knockout Mice; Link; Lipodystrophy; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Muscle; Mutation; Nature; Nuclear Translocation; PTEN gene; Pancreas; Pathologic; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Physiological; Point Mutation; Proinsulin; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Resistance; Role; SHORT syndrome; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Syndrome; System; TNFRSF5 gene; Tissues; United States National Institutes of Health; Work; biological adaptation to stress; cell growth; endoplasmic reticulum stress; glucose metabolism; glucose uptake; improved; in vivo; insulin regulation; insulin sensitivity; insulin signaling; lipid metabolism; mouse model; muscle form; mutant; novel; p38 Mitogen Activated Protein Kinase; protein metabolism; proteostasis; response; src Homology Region 2 Domain; stoichiometry; stress kinase; transcription factor

Project Summary/Abstract This is a revised competitive renewal of NIH grant DK055545 which is focused on the role of phosphatidylinositol 3-kinase (PI3K) in insulin action and insulin resistance. PI 3-kinase is a critical node in insulin's metabolic actions. Alterations in PI3K have been implicated in cancer, diabetes and many other disorders. In previous work under this grant we have used both in vitro and in vivo approaches to define the role of this enzyme in insulin action and insulin resistance. We have shown that regulation of PI3K depends both on the nature of the different regulatory subunits; the stoichiometry between regulatory and catalytic subunits; the ability of PI 3-kinase to serve as a site for divergence of downstream signaling; and alterations in PI3K activity in disease states. We have also identified new links between the PI 3-kinase pathway and other signaling pathways, including important links between the p85 regulatory subunits and several pathways involved in insulin resistance, such as activation of the stress kinases JNK and p38, regulation of the PIP3 phosphatase PTEN, and a novel link between PI 3-kinase, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) created by the interaction between p85α and XBP-1s, facilitating XBP-1s transport into the nucleus and thus modifying the ER stress response. Another exciting recent development has been the identification of a mutation in p85α in patients with SHORT syndrome, a syndrome characterized by insulin resistance and partial lipodystrophy. Recently, we have created a knock-in mouse bearing this mutation to study its effects in vivo. We have also begun to characterize the different roles of the two major catalytic subunits of PI3K (p110α and p110β) in insulin signaling and mitochondrial homeostasis through knockout in vivo and in vitro. This has led to new hypotheses about the unique roles of the different catalytic and regulatory subunits of PI 3-kinase, which allow these proteins to serve as both sites of divergence in the insulin signaling pathway and sites of positive and negative regulation in physiological and pathological states. In the next five years, we propose to expand upon these observations by defining at both the molecular and physiological levels how different signals are generated by the p110α and p110β catalytic subunits of PI 3- kinase, the specific signaling complexes involved, and the link between PI3K and mitochondrial homeostasis. In addition, we will expand our studies on the regulatory subunits focusing defining the regions of p85α that interact with XBP-1s creating crosstalk between the PI 3-kinase pathway and ER stress. We will also further define how mutations in the p85α regulatory subunit can have a dominant negative effect and result in severe insulin resistance. Together, these studies will help complete our understanding of the role of the PI3K system and its different catalytic and regulatory subunits in insulin action and insulin resistance.

项目摘要/摘要 这是NIH资助金DK055545的修订后的竞争性续签，重点是 磷脂酰肌醇3-激酶(PI3K)在胰岛素作用和胰岛素抵抗中的作用。磷脂酰肌醇3-激酶是细胞内的关键节点 胰岛素的新陈代谢作用。PI3K的变化与癌症、糖尿病和许多其他疾病有关 精神错乱。在之前的这项资助下的工作中，我们使用了体外和体内的方法来定义 这种酶在胰岛素作用和胰岛素抵抗中的作用。我们已经证明，对PI3K的调节取决于 都是关于不同调控亚单位的性质；调控和催化之间的化学计量 亚基；PI 3-激酶作为下游信号分流的位置的能力；以及 疾病状态下的PI3K活性。我们还发现了PI3-激酶途径和其他 信号通路，包括P85调节亚基和几个通路之间的重要联系 参与胰岛素抵抗，如应激激酶JNK和p38的激活，PIP3的调节 磷酸酶PTEN，以及PI-3-K、内质网(ER)应激和未折叠之间的新联系 P85α和XBP-1S相互作用所产生的蛋白质反应，促进XBP-1S转运到 从而改变内质网应激反应。另一个令人兴奋的最新发展是 矮小综合征患者P85α突变的鉴定 抵抗力和部分性脂营养不良。最近，我们创造了一只携带这种突变的基因敲除小鼠 研究其在体内的作用。我们也开始研究这两种主要催化剂的不同作用。 胰岛素信号转导中PI3K亚单位(p110α和p110β)与线粒体动态平衡 体内和体外。这导致了关于不同催化和调节的独特作用的新假说 PI 3-激酶的亚基，使这些蛋白成为胰岛素信号转导的两个分歧点 生理和病理状态下正负调控的途径和部位。 在接下来的五年里，我们建议通过在两个分子上定义 以及生理水平PI 3的p110α和p110β催化亚基如何产生不同的信号 PI3K与线粒体动态平衡之间的联系。 此外，我们将扩大对调节亚基的研究，重点定义P85α的区域 与XBP-1相互作用，在PI 3-激酶通路和内质网应激之间产生串扰。我们还将进一步 明确p85α调节亚单位的突变如何产生显性负面影响并导致严重的 胰岛素抵抗。总而言之，这些研究将有助于我们完成对PI3K系统作用的理解 及其不同的催化和调节亚基在胰岛素作用和胰岛素抵抗中的作用。

项目成果

Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase.

• DOI: 10.1167/iovs.16-21347
• 发表时间: 2017-06-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Solheim MH;Clermont AC;Winnay JN;Hallstensen E;Molven A;Njølstad PR;Rødahl E;Kahn CR
• 通讯作者: Kahn CR

PI 3-kinase regulatory subunits as regulators of the unfolded protein response.

• DOI: 10.1016/b978-0-12-385114-7.00009-x
• 发表时间: 2011
• 期刊: METHODS IN ENZYMOLOGY
• 作者: Winnay, Jonathon N.;Kahn, C. Ronald
• 通讯作者: Kahn, C. Ronald

A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to modulate the unfolded protein response.

• DOI: 10.1038/nm.2121
• 发表时间: 2010-04
• 期刊: Nature medicine
• 影响因子: 82.9

Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism.

• DOI: 10.1172/jci23187
• 发表时间: 2005-03
• 期刊: The Journal of clinical investigation
• 作者: C. Taniguchi;K. Ueki;R. Kahn

Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.

• DOI: 10.1016/j.cmet.2010.02.002
• 发表时间: 2010-03-03
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Sopasakis VR;Liu P;Suzuki R;Kondo T;Winnay J;Tran TT;Asano T;Smyth G;Sajan MP;Farese RV;Kahn CR;Zhao JJ
• 通讯作者: Zhao JJ