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Typus
Verschleierung
Bearbeiter
Hindemith
Gesichtet
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Untersuchte Arbeit:
Seite: 14, Zeilen: 1-28
Quelle: McCarthy and Elmendorf 2007
Seite(n): 378, 379, Zeilen: 378: l.col: 26ff; 379: l.col: 17ff
[Furthermore, expression of] constitutively active aPKC recapitulates the effects of insulin on GLUT4 translocation and glucose transport.

1.3.7 PI3-K independent pathway

It is well established that activation of GLUT4 translocation by insulin requires a PI3K signal involving the upstream IR and IRS activators and the downstream Akt and PKC target enzymes and AS160 protein. Some studies over the past decade have also suggested that a second pathway occurs as a consequence of Cbl tyrosine phosphorylation (57), (58). Cbl and the adaptor protein CAP are recruited to the insulin receptor by APS (59). Once tyrosine phosphorylated by the receptor, Cbl can recruit the adaptor protein CrkII to lipid rafts, along with the guanyl nucleotide exchange factor C3G (60). C3G can then activate the GTP-binding protein TC10, which resides in lipid rafts . The correct spatial compartmentalization of these signaling molecules in the lipid raft microdomain appears to be essential or insulinstimulated GLUT4 translocation and glucose transport, as these insulin-mediated events are abolished by dominant-interfering mutants of CAP that prevent the localization of Cbl to lipid rafts (61). Nevertheless, investigation suggests a role of TC10 in the regulation of actin dynamics and phosphoinositides. Cellular cortical actin exists in two forms: monomeric globular actin (G-actin) and filamentous actin (F-actin). In the case of cytosketal fusion, microtubules and cortical actin plays the important role. When the actin network (62) in skeletal muscle is treated with actin depolymerizing agent cytochalasin D or the actin monomer binding red sea sponge toxins Latrunculin A or B, it leads to the inhibition of glucose uptake and GLUT4 translocation (63). Two potentially overlapping models hypothesizing the role of actin in glucose uptake. According to the first one, insulin causes cortical actin remodeling, such that incoming vesicles can travel through the peripheral actin mesh to fuse with the plasma membrane (64) . The second suggests that actin filaments function as “highways,” upon which vesicles travel to reach the plasma membrane. Regardless of the exact actin function, it is apparent that insulin signaling to rearrange cortical actin represents a required pathway for optimal movement or fusion of GLUT4-containing vesicles and plasma membranes.


57. Ribon,V, Saltiel,AR: Insulin stimulates tyrosine phosphorylation of the protooncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem.J. 324 ( Pt 3):839-845, 1997

58. Liu,J, DeYoung,SM, Hwang,JB, O'Leary,EE, Saltiel,AR: The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. J.Biol.Chem. 278:36754-36762, 2003

59. Liu,J, Kimura,A, Baumann,CA, Saltiel,AR: APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol.Cell Biol. 22:3599-3609, 2002

60. Chiang,SH, Baumann,CA, Kanzaki,M, Thurmond,DC, Watson,RT, Neudauer,CL, Macara,IG, Pessin,JE, Saltiel,AR: Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410:944-948, 2001

61. Baumann,CA, Ribon,V, Kanzaki,M, Thurmond,DC, Mora,S, Shigematsu,S, Bickel,PE, Pessin,JE, Saltiel,AR: CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407:202-207, 2000

62. Omata,W, Shibata,H, Li,L, Takata,K, Kojima,I: Actin filaments play a critical role in insulin-induced exocytotic recruitment but not in endocytosis of GLUT4 in isolated rat adipocytes. Biochem.J. 346 Pt 2:321-328, 2000

63. Brozinick,JT, Jr., Hawkins,ED, Strawbridge,AB, Elmendorf,JS: Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in glucose transporter 4 translocation in insulin-sensitive tissues. J.Biol.Chem. 279:40699-40706, 2004

64. Jiang,ZY, Chawla,A, Bose,A, Way,M, Czech,MP: A phosphatidylinositol 3-kinaseindependent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling. J.Biol.Chem. 277:509-515, 2002

Furthermore, expression of constitutively active aPKC recapitulates the effects of insulin on GLUT4 translocation and glucose transport. [...]

PI3K-independent signaling: It is well established that activation of GLUT4 translocation by insulin requires a PI3K signal involving the upstream IR and IRS activators and the downstream Akt and PKC target enzymes and AS160 protein as presented above (Fig.A). Some studies over the past decade have also suggested that a second pathway (Fig.B) occurs as a consequence of Cbl tyrosine phosphorylation59,60. Cbl and the adaptor protein CAP are recruited to the insulin receptor by APS61. Once tyrosine phosphorylated by the receptor, Cbl can recruit the adaptor protein CrkII to lipid rafts, along with the guanyl nucleotide exchange factor C3G62. C3G can then activate the GTP-binding protein TC10, which resides in lipid rafts63. The correct spatial compartmentalization of these signaling molecules in the lipid raft microdomain appears to be essential for insulin-stimulated GLUT4 translocation and glucose transport, as these insulin-mediated events are abolished by dominant-interfering mutants of CAP that prevent the localization of Cbl to lipid rafts64. [...]

Nevertheless, investigation suggests a role of TC10 in the regulation of actin dynamics69-74 and phosphoinositides75.

[page 379]

Cortical actin: Cellular cortical actin exists in two forms: monomeric globular actin (G-actin) and filamentous actin (F-actin).[...] Disrupting the actin network in cultured cells or in intact rat skeletal muscle with the actin-depolymerizing agent cytochalasin D, or the actin monomer binding Red Sea Sponge toxins Latrunculin A or B, inhibits insulin-stimulated GLUT4 translocation and glucose uptake77,80,81. [...] Overall, these studies have given rise to two potentially overlapping models hypothesizing the role of actin in glucose uptake. The first proposes that insulin causes cortical actin remodeling, such that incoming vesicles can travel through the peripheral actin mesh to fuse with the plasma membrane. The second suggests that actin filaments function as “highways,” upon which vesicles travel to reach the plasma membrane71. Regardless of the exact actin function, it is apparent that insulin signaling to rearrange cortical actin represents a required pathway for optimal movement or fusion of GLUT4-containing vesicles and plasma membranes.


59. Ribon V, Saltiel AR. Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem J 1997; 324 : 839-45.

60. Liu J, DeYoung SM, Hwang JB, O’Leary EE, Saltiel AR. The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport. J Biol Chem 2003; 278 : 36754-62.

61. Liu J, Kimura A, Baumann CA, Saltiel AR. APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol Cell Biol 2002; 22 : 3599-609.

62. Chiang SH, Baumann CA, Kanzaki M, Thurmond DC, Watson RT, Neudauer CL, et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 2001; 410 : 944-8.

63. Watson RT, Shigematsu S, Chiang SH, Mora S, Kanzaki M, Macara IG, et al. Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation. J Cell Biol 2001; 154 : 829-40.

64. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S, Shigematsu S, et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 2000; 407 : 202-7.

69. Chunqiu Hou J, Pessin JE. Lipid Raft targeting of the TC10 amino terminal domain is responsible for disruption of adipocyte cortical actin. Mol Biol Cell 2003; 14 : 3578-91.

70. Inoue M, Chang L, Hwang J, Chiang SH, Saltiel AR. The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 2003; 422 : 629-33.

71. Jiang ZY, Chawla A, Bose A, Way M, Czech MP. A phosphatidylinositol 3-kinase-independent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling. J Biol Chem 2002; 277 : 509-15.

72. Kanzaki M, Pessin JE. Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. J Biol Chem 2001; 276 : 42436-44.

73. Kanzaki M, Pessin JE. Caveolin-associated filamentous actin (Cav-actin) defines a novel F-actin structure in adipocytes. J Biol Chem 2002; 277 : 25867-9.

74. Kanzaki M, Watson RT, Hou JC, Stamnes M, Saltiel AR, Pessin JE. Small GTP-binding protein TC10 differentially regulates two distinct populations of filamentous actin in 3T3L1 adipocytes. Mol Biol Cell 2002; 13 : 2334-46.

75. Maffucci T, Brancaccio A, Piccolo E, Stein RC, Falasca M. Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO J 2003; 22 : 4178-89.

77. Tsakiridis T, Vranic M, Klip A. Disassembly of the actin network inhibits insulin-dependent stimulation of glucose transport and prevents recruitment of glucose transporters to the plasma membrane. J Biol Chem 1994; 269 : 29934-42.

80. Omata W, Shibata H, Li L, Takata K, Kojima I. Actin filaments play a critical role in insulin-induced exocytotic recruitment but not in endocytosis of GLUT4 in isolated rat adipocytes. Biochem J 2000; 346 : 321-8.

81. Brozinick JT, Jr., Hawkins ED, Strawbridge AB, Elmendorf JS. Disruption of cortical actin in skeletal muscle demonstrates an essential role of the cytoskeleton in glucose transporter 4 translocation in insulin-sensitive tissues. J Biol Chem 2004; 279 : 40699-706.

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