APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor
Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical mo...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714002939 |
| _version_ | 1818155927786749952 |
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| author | Jiyoon Ryu Amanda K. Galan Xiaoban Xin Feng Dong Muhammad A. Abdul-Ghani Lijun Zhou Changhua Wang Cuiling Li Bekke M. Holmes Lauren B. Sloane Steven N. Austad Shaodong Guo Nicolas Musi Ralph A. DeFronzo Chuxia Deng Morris F. White Feng Liu Lily Q. Dong |
| author_facet | Jiyoon Ryu Amanda K. Galan Xiaoban Xin Feng Dong Muhammad A. Abdul-Ghani Lijun Zhou Changhua Wang Cuiling Li Bekke M. Holmes Lauren B. Sloane Steven N. Austad Shaodong Guo Nicolas Musi Ralph A. DeFronzo Chuxia Deng Morris F. White Feng Liu Lily Q. Dong |
| author_sort | Jiyoon Ryu |
| collection | DOAJ |
| description | Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways. |
| first_indexed | 2024-12-11T14:50:11Z |
| format | Article |
| id | doaj.art-98b154f5d07a41fa93dfe06c7416fa4c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T14:50:11Z |
| publishDate | 2014-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-98b154f5d07a41fa93dfe06c7416fa4c2022-12-22T01:01:30ZengElsevierCell Reports2211-12472014-05-01741227123810.1016/j.celrep.2014.04.006APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin ReceptorJiyoon Ryu0Amanda K. Galan1Xiaoban Xin2Feng Dong3Muhammad A. Abdul-Ghani4Lijun Zhou5Changhua Wang6Cuiling Li7Bekke M. Holmes8Lauren B. Sloane9Steven N. Austad10Shaodong Guo11Nicolas Musi12Ralph A. DeFronzo13Chuxia Deng14Morris F. White15Feng Liu16Lily Q. Dong17Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USAMammalian Genetics Section, GDDB, NIDDK, National Institutes of Health, Bethesda, MD 20892, USADepartment of Physiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADivision of Molecular Cardiology, Texas A&M University, Temple, TX 76504, USADepartment of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Medicine, University of Texas Health Science Center, San Antonio, TX 78229-3900, USAMammalian Genetics Section, GDDB, NIDDK, National Institutes of Health, Bethesda, MD 20892, USADivision of Endocrinology, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USADepartment of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USABinding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways.http://www.sciencedirect.com/science/article/pii/S2211124714002939 |
| spellingShingle | Jiyoon Ryu Amanda K. Galan Xiaoban Xin Feng Dong Muhammad A. Abdul-Ghani Lijun Zhou Changhua Wang Cuiling Li Bekke M. Holmes Lauren B. Sloane Steven N. Austad Shaodong Guo Nicolas Musi Ralph A. DeFronzo Chuxia Deng Morris F. White Feng Liu Lily Q. Dong APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor Cell Reports |
| title | APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor |
| title_full | APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor |
| title_fullStr | APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor |
| title_full_unstemmed | APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor |
| title_short | APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor |
| title_sort | appl1 potentiates insulin sensitivity by facilitating the binding of irs1 2 to the insulin receptor |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714002939 |
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