インスリン受容体

索引トップ用語の索引ランキングカテゴリー

出典: フリー百科事典『ウィキペディア（Wikipedia）』 (2023/04/28 20:08 UTC 版)

病理

インスリン受容体の活性化の主要な役割は、グルコースの取り込みの誘導である。そのため、「インスリン非感受性」もしくはインスリン受容体シグナル伝達の低下によって細胞はグルコースを取り込むことができなくなり、2型糖尿病がもたらされる。その帰結は高血糖と、糖尿病に起因するすべての後遺症である。

インスリン抵抗性の患者は黒色表皮腫（英語版）を発症することがある。INSR遺伝子のホモ接合変異によって、ドナヒュー症候群（英語版） (妖精症) が引き起こされる。この常染色体劣性異常によって、インスリン受容体は完全に機能を持たなくなる。患者には、低位置でしばしば突出した耳、怒り鼻、厚い唇、そして重度の発育遅滞がみられる。ほとんどの場合予後は極めて悪く、出生後1年以内に死に至る。同じ遺伝子の他の変異では、より重症度の低いラブソン-メンデンホール症候群（英語版）が引き起こされ、患者には特徴的な歯の異常、歯肉の肥大、松果体の増大がみられる。どちらの疾患でも血中グルコース濃度の大幅な変動が見られ、食事後にいったん極めて高値となり、その後異常な低値まで急速に低下する^[19]。

相互作用

インスリン受容体はこれらと相互作用することが示されている。

ENPP1（英語版）^[20]
GRB10（英語版）^[21]^[22]^[23]^[24]^[25]
GRB7（英語版）^[26]
IRS1^[27]^[28]
MAD2L1（英語版）^[29]
PRKCD（英語版）^[30]^[31]
PTPN11^[32]^[33]
SH2B1（英語版）^[34]^[35]

注釈

^ ただし細胞にグルコースを取り込むトランスポータにも何種類か存在しており、GLUT1やGLUT2のようにインスリンのシグナルとは無関係に細胞外からグルコースを取り込むトランスポータも存在する。逆に、GLUT4のように、インスリンのシグナルが入ると動き出して高効率でグルコースを取り込むトランスポータも存在する。

出典

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000171105 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000005534 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ ^a ^b “Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor”. BioEssays 31 (4): 422–34. (April 2009). doi:10.1002/bies.200800210. PMID 19274663.
^ “The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signalling”. Cell 40 (4): 747–58. (April 1985). doi:10.1016/0092-8674(85)90334-4. PMID 2859121.
^ “Proinsulin binds with high affinity the insulin receptor isoform A and predominantly activates the mitogenic pathway”. Endocrinology 153 (5): 2152–63. (May 2012). doi:10.1210/en.2011-1843. PMID 22355074.
^ ^a ^b “Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease”. Endocrine Reviews 30 (6): 586–623. (October 2009). doi:10.1210/er.2008-0047. PMID 19752219.
^ “Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms”. The Biochemical Journal 440 (3): 397–403. (December 2011). doi:10.1042/BJ20110550. PMID 21838706.
^ ^a ^b ^c “Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists”. Proceedings of the National Academy of Sciences of the United States of America 107 (15): 6771–6. (April 2010). Bibcode: 2010PNAS..107.6771S. doi:10.1073/pnas.1001813107. PMC 2872410. PMID 20348418.
^ ^a ^b “Structure of the insulin receptor ectodomain reveals a folded-over conformation”. Nature 443 (7108): 218–21. (September 2006). Bibcode: 2006Natur.443..218M. doi:10.1038/nature05106. PMID 16957736.
^ “Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor”. The Journal of Cell Biology 217 (5): 1643–1649. (May 2018). doi:10.1083/jcb.201711047. PMID 29453311.
^ ^a ^b ^c “Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation”. Molecular Systems Biology 5 (5): 243. (Feb 2009). doi:10.1038/msb.2008.78. PMC 2657531. PMID 19225456.
^ ^a ^b “Insulin interactions with its receptors: experimental evidence for negative cooperativity”. Biochemical and Biophysical Research Communications 55 (1): 154–61. (November 1973). doi:10.1016/S0006-291X(73)80072-5. PMID 4361269.
^ Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert; Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert (2002). Biochemistry (5th ed.). W H Freeman. ISBN 0716730510
^ “Insulin degradation: progress and potential”. Endocrine Reviews 19 (5): 608–24. (October 1998). doi:10.1210/er.19.5.608. PMID 9793760.
^ “Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection”. Cell Metabolism. (August 2018). doi:10.1016/j.cmet.2018.08.003. PMID 30174303.
^ “The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity”. Journal of Immunology 198 (5): 1910–1920. (March 2017). doi:10.4049/jimmunol.1601011. PMID 28115529.
^ “Genotype-phenotype correlation in inherited severe insulin resistance”. Human Molecular Genetics 11 (12): 1465–75. (June 2002). doi:10.1093/hmg/11.12.1465. PMID 12023989.
^ “Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit”. Diabetes 49 (1): 13–9. (January 2000). doi:10.2337/diabetes.49.1.13. PMID 10615944.
^ “Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family”. Oncogene 19 (25): 2895–903. (June 2000). doi:10.1038/sj.onc.1203616. PMID 10871840.
^ “Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus”. The Journal of Biological Chemistry 271 (15): 8882–6. (April 1996). doi:10.1074/jbc.271.15.8882. PMID 8621530.
^ “Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function”. Proceedings of the National Academy of Sciences of the United States of America 92 (22): 10287–91. (October 1995). Bibcode: 1995PNAS...9210287L. doi:10.1073/pnas.92.22.10287. PMC 40781. PMID 7479769.
^ “Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains”. The Journal of Biological Chemistry 273 (12): 6860–7. (March 1998). doi:10.1074/jbc.273.12.6860. PMID 9506989.
^ “Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains”. The Journal of Biological Chemistry 272 (5): 2659–67. (January 1997). doi:10.1074/jbc.272.5.2659. PMID 9006901.
^ “Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2”. Oncogene 19 (16): 2052–9. (April 2000). doi:10.1038/sj.onc.1203469. PMID 10803466.
^ “Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action”. The Journal of Biological Chemistry 277 (2): 1531–7. (January 2002). doi:10.1074/jbc.M101521200. PMID 11606564.
^ “Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786”. The Journal of Biological Chemistry 271 (11): 5980–3. (March 1996). doi:10.1074/jbc.271.11.5980. PMID 8626379.
^ “Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation”. The Journal of Biological Chemistry 272 (15): 10035–40. (April 1997). doi:10.1074/jbc.272.15.10035. PMID 9092546.
^ “Insulin induces specific interaction between insulin receptor and protein kinase C delta in primary cultured skeletal muscle”. Molecular Endocrinology 15 (4): 565–74. (April 2001). doi:10.1210/mend.15.4.0612. PMID 11266508.
^ “Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling”. Diabetes 51 (6): 1921–30. (June 2002). doi:10.2337/diabetes.51.6.1921. PMID 12031982.
^ “Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro”. Biochemical and Biophysical Research Communications 199 (2): 780–5. (March 1994). doi:10.1006/bbrc.1994.1297. PMID 8135823.
^ “Adapter function of protein-tyrosine phosphatase 1D in insulin receptor/insulin receptor substrate-1 interaction”. The Journal of Biological Chemistry 270 (49): 29189–93. (December 1995). doi:10.1074/jbc.270.49.29189. PMID 7493946.
^ “SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase”. The Biochemical Journal 335 ( Pt 1) (1): 103–9. (October 1998). doi:10.1042/bj3350103. PMC 1219757. PMID 9742218.
^ “Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain”. Mammalian Genome 10 (12): 1160–7. (December 1999). doi:10.1007/s003359901183. PMID 10594240.