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Typus
Verschleierung
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 13, Zeilen: 1-7, 12-33
Quelle: McCarthy and Elmendorf 2007
Seite(n): 375, 377, 378, Zeilen: 375: l.col: 31ff; 377: l.col5ff; 378: l.col: 17ff
Insulin binding to the two high-affinity extracellular α subunits leads to activation of intrinsic tyrosine kinase activity of the transmembrane β subunits and autophosphorylation of specific tyrosine residues (44), (45). Phosphorylation enhances tyrosine kinase activity of the b subunits towards a host of proteins including members of the insulin receptor substrate family (IRS-1, -2, -3, -4, -5, and -6), Cbl, SIRP (signal regulatory protein) family members, and APS [adapter protein containing a pleckstrin homology (PH) and Src-homology 2 (SH2) domain , (46). [...]

[...]

Insulin-dependent tyrosine phosphorylation of IRS-1/2 creates docking sites for downstream effector molecules including Class IA PI3K. Activated PI3K catalyzes the phosphorylation of PI-P2 on the 3 position of the inositol ring, forming PI-P3. Increased membrane PI-P3 is crucial for insulin-stimulated GLUT4 translocation, as this phospholipid provides docking sites for downstream molecules via their pleckstrin homology (PH) domains. Inhibition of PI-P3 formation with wortmannin or LY29004 effectively blocks insulin-stimulated GLUT4 translocation and glucose transport (47), (48) . Phosphatase regulators of PI3K generated lipids include PTEN and SHIP2. The PTEN catalyzes the dephosphorylation of phosphatidylinositols at the D3 position, while the latter catalyzes dephosphorylation of PI - P3 to yield PI -P2 (49). PI -P3 formation mediates the plasma membrane translocation of two PH domain containing proteins which is important for insulin-regulated glucose uptake: Akt (protein kinase B, PKB) and phosphoinositide-dependent-kinase-1 (PDK1). PDK2 is recently identified as the protein kinase mTOR (mammalian target of rapamycin) complexed to the regulatory protein rictor (50). There are three isoforms of protein kinase AKT (1-3) (51) in which GLUT4 translocation is dependent on AKT2 (52). AKT2 acts through it downstream molecule AS160 (53). AS160 contains a GTPase activating domain for Rabs, small G proteins which is involved in the vesicle trafficking (54), (55). Along with recruiting and activating Akt, PI 3,4,5-P3 formation in concert with PDK1 also leads to the activation of atypical protein kinase C (aPKC), and both aPKC isoforms z and l [sic] have been implicated in GLUT4 translocation (56). PKC knockout models and expression of kinase-inactive PKC-z/l [sic] inhibits GLUT4 translocation and glucose uptake in a variety of cell types, and this phenotype can be reversed in PKC-l–/– [sic] cells by expressing wild-type aPKC.


44. Bjornholm,M, Zierath,JR: Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem.Soc.Trans. 33:354-357, 2005

45. Luo,RZ, Beniac,DR, Fernandes,A, Yip,CC, Ottensmeyer,FP: Quaternary structure of the insulin-insulin receptor complex. Science 285:1077-1080, 1999

46. Rocchi,S, Tartare-Deckert,S, Murdaca,J, Holgado-Madruga,M, Wong,AJ, Van Obberghen,E: Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. Mol.Endocrinol. 12:914-923, 1998

47. Okada,T, Kawano,Y, Sakakibara,T, Hazeki,O, Ui,M: Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J.Biol.Chem. 269:3568- 3573, 1994

48. Clarke,JF, Young,PW, Yonezawa,K, Kasuga,M, Holman,GD: Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3- kinase inhibitor, wortmannin. Biochem.J. 300 ( Pt 3):631-635, 1994

49. Scheid,MP, Woodgett,JR: Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 546:108-112, 2003

50. Sarbassov,DD, Guertin,DA, Ali,SM, Sabatini,DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101, 2005

51. Bae,SS, Cho,H, Mu,J, Birnbaum,MJ: Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J.Biol.Chem. 278:49530-49536, 2003

52. Calera,MR, Martinez,C, Liu,H, Jack,AK, Birnbaum,MJ, Pilch,PF: Insulin increases the association of Akt-2 with Glut4-containing vesicles. J.Biol.Chem. 273:7201-7204, 1998

53. Kane,S, Sano,H, Liu,SC, Asara,JM, Lane,WS, Garner,CC, Lienhard,GE: A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J.Biol.Chem. 277:22115-22118, 2002

54. Sano,H, Kane,S, Sano,E, Miinea,CP, Asara,JM, Lane,WS, Garner,CW, Lienhard,GE: Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J.Biol.Chem. 278:14599-14602, 2003

55. Jordens,I, Marsman,M, Kuijl,C, Neefjes,J: Rab proteins, connecting transport and vesicle fusion. Traffic. 6:1070-1077, 2005

56. Farese,RV, Sajan,MP, Standaert,ML: Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp.Biol.Med.(Maywood.) 230:593-605, 2005

Insulin binding to the two high-affinity extracellular a [sic] subunits leads to activation of intrinsic tyrosine kinase activity of the transmembrane β subunits and autophosphorylation of specific tyrosine residues1,16. Phosphorylation enhances tyrosine kinase activity of the β subunits towards a host of proteins including members of the insulin receptor substrate family (IRS-1, -2, -3, -4, -5, and -6), Gab-1, Shc, p62dok, Cbl, SIRP (signal regulatory protein) family members, and APS [adapter protein containing a pleckstrin homology (PH) and Src-homology 2 (SH2) domain]17-23.

[...]

PI3K-dependent signaling: Insulin-dependent tyrosine phosphorylation of IRS-1/2 creates docking sites for downstream effector molecules including Class IA PI3K32.

[page 377]

[...] Activated PI3K catalyzes the phosphorylation of PI 4,5-P2 on the 3 position of the inositol ring, forming PI 3,4,5-P3. Increased membrane PI 3,4,5-P3 is essential for insulin-stimulated GLUT4 translocation, as this phospholipid provides docking sites for downstream molecules via their pleckstrin homology (PH) domains. Inhibiting the formation of PI 3,4,5-P3 with wortmannin or LY29004 effectively blocks insulin-stimulated GLUT4 translocation and glucose transport33,34. Phosphatase regulators of PI3K generated lipids include PTEN and SHIP2. The former catalyzes the dephosphorylation of phosphatidylinositols at the D3 position, while the latter catalyzes dephosphorylation of PI 3,4,5-P3 to yield PI 3,4-P2 35.

PI 3,4,5-P3 formation mediates the plasma membrane translocation of two PH domaincontaining proteins crucial for insulin-regulated glucose uptake: Akt (protein kinase B, PKB) and phosphoinositide-dependent-kinase-1 (PDK1)35. Following membrane recruitment, the 60 kDa serine/threonine kinase Akt is phosphorylated at two key sites, threonine 308 (Thr308) and serine 473 (Ser473), resulting in enzyme activation. Ser473 phosphorylation occurs first and is accomplished by the once elusive PDK2, which was recently identified as the protein kinase mTOR (mammalian target of rapamycin) complexed to the regulatory protein rictor36-38.[...]

There are three existing Akt isoforms (Akt1-3)41, and studies have identified Akt2 as the relevant isoform in insulin-stimulated GLUT4 translocation. [...]

[...] Also, a number of key properties of the protein have since been elucidated. First, AS160 contains a GTPaseactivating domain (GAP) for Rabs, small G proteins involved in vesicle trafficking49,53.

[page 378]

Along with recruiting and activating Akt, PI 3,4,5-3 formation in concert with PDK1 also leads to the activation of atypical protein kinase C (aPKC), and both aPKC isoforms ζ and λ have been implicated in GLUT4 translocation. As recently reviewed58, aPKC knockout models and expression of kinase-inactive PKC-ζ/λ inhibits GLUT4 translocation and glucose uptake in a variety of cell types, and this phenotype can be reversed in PKC-λ–/– cells by expressing wild-type aPKC.


1. Bjornholm M, Zierath JR. Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem Soc Trans 2005; 33 : 354-7.

16. Luo RZ, Beniac DR, Fernandes A, Yip CC, Ottensmeyer FP. Quaternary structure of the insulin-insulin receptor complex. Science 1999; 285 : 1077-80.

17. Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 1992; 70 : 93-104.

18. Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 1996; 379 : 560-4.

19. Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, et al. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Mol Cell Biol 1996; 16 : 6887-99.

20. White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem 1998; 182 : 3-11.

21. Rocchi S, Tartare-Deckert S, Murdaca J, Holgado-Madruga M, Wong AJ, Van Obberghen E. Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. Mol Endocrinol 1998; 12 : 914-23.

22. Moodie SA, Alleman-Sposeto J, Gustafson TA. Identification of the APS protein as a novel insulin receptor substrate. J Biol Chem 1999; 274 : 11186-93.

23. Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE. Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 2003; 278 : 25323-30.

32. Shepherd PR. Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta Physiol Scand 2005; 183 : 3-12.

33. Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M. Essential role of phosphatidylinositol 3-kinase in insulininduced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem 1994; 269 : 3568-73.

34. Clarke JF, Young PW, Yonezawa K, Kasuga M, Holman GD. Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem J 1994; 300 : 631-5.

35. Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 2003; 546: 108-12.

36. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictormTOR complex. Science 2005; 307 : 1098-101.

37. Sarbassov dos D, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17 : 596-603.

38. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124 : 471-84.

41. Bae SS, Cho H, Mu J, Birnbaum MJ. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/ protein kinase B. J Biol Chem 2003; 278 : 49530-6.

49. Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, et al. Insulin-stimulated phosphorylation of a Rab GTPaseactivating protein regulates GLUT4 translocation. J Biol Chem 2003; 278 : 14599-602.

53. Jordens I, Marsman M, Kuijl C, Neefjes J. Rab proteins, connecting transport and vesicle fusion. Traffic 2005; 6 : 1070-7.

58. Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood) 2005; 230 : 593-605.

Anmerkungen

The source is not given.

Note that in the dissertation one finds "z and l" instead of "ζ and λ", and sub-/superscripts that have disappeared. Copying and pasting from a PDF file often leads to this kind of a mistake.

Sichter
(Hindemith), WiseWoman

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