scholarly journals Interleukin-3-mediated Cell Survival Signals Include Phosphatidylinositol 3-Kinase-dependent Translocation of the Glucose Transporter GLUT1 to the Cell Surface

2003 ◽  
Vol 278 (41) ◽  
pp. 39337-39348 ◽  
Author(s):  
Johanne Bentley ◽  
Dalina Itchayanan ◽  
Kay Barnes ◽  
Elizabeth McIntosh ◽  
Xiuwen Tang ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Survival ◽  
Glucose Transporter ◽  
Phosphatidylinositol 3 Kinase ◽  
Interleukin 3 ◽  
Glucose Transporter Glut1 ◽  
Transporter Glut1 ◽  
Phosphatidylinositol 3 ◽  
Survival Signals

Insulin-induced actin filament remodeling colocalizes actin with phosphatidylinositol 3-kinase and GLUT4 in L6 myotubes

2000 ◽  
Vol 113 (2) ◽  
pp. 279-290 ◽  
Author(s):  
Z.A. Khayat ◽  
P. Tong ◽  
K. Yaworsky ◽  
R.J. Bloch ◽  
A. Klip
Keyword(s):  
Cell Surface ◽  
Glucose Transporter ◽  
Insulin Treatment ◽  
Surface Membrane ◽  
Dorsal Surface ◽  
Regulatory Subunit ◽  
Phosphatidylinositol 3 Kinase ◽  
L6 Myotubes ◽  
Triton X ◽  
Phosphatidylinositol 3

We examined the temporal reorganization of actin microfilaments by insulin and its participation in the localization of signaling molecules and glucose transporters in L6 myotubes expressing myc-tagged glucose transporter 4 (GLUT4myc). Scanning electron microscopy revealed a dynamic distortion of the dorsal cell surface (membrane ruffles) upon insulin treatment. In unstimulated cells, phalloidin-labeled actin filaments ran parallel to the longitudinal axis of the cell. Immunostaining of the p85 regulatory subunit of phosphatidylinositol 3-kinase was diffusely punctate, and GLUT4myc was perinuclear. After 3 minutes of insulin treatment, actin reorganized to form structures; these structures protruded from the dorsal surface of the myotubes by 10 minutes and condensed in the myoplasm into less prominent foci at 30 minutes. The p85 polypeptide colocalized with these structures at all time points. Actin remodeling and p85 relocalization to actin structures were prevented by cytochalasin D or latrunculin B. GLUT4myc recruitment into the actin-rich projections was also observed, but only after 10 minutes of insulin treatment. Irrespective of insulin stimulation, the majority of p85 and a portion (45%) of GLUT4 were recovered in the Triton X-100-insoluble material that was also enriched with actin. In contrast, vp165, a transmembrane aminopeptidase that morphologically colocalized with GLUT4 vesicles, was fully soluble in Triton X-100 extracts of both insulin-treated and control myotubes. Transient transfection of dominant inhibitory Rac1 (N17) into L6 myotubes prevented formation of dorsal actin structures and blocked insulin-induced GLUT4myc translocation to the cell surface. We propose that insulin-dependent formation of actin structures facilitates the association of PI3-K (p85) with GLUT4 vesicles and, potentially, the arrival of GLUT4 at the cell surface.

scholarly journals Apoptosis Suppression by Raf-1 and MEK1 Requires MEK- and Phosphatidylinositol 3-Kinase-Dependent Signals

2001 ◽  
Vol 21 (7) ◽  
pp. 2324-2336 ◽  
Author(s):  
Alexander von Gise ◽  
Petra Lorenz ◽  
Claudia Wellbrock ◽  
Brian Hemmings ◽  
Friederike Berberich-Siebelt ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cell Line ◽  
Active Form ◽  
Dominant Negative ◽  
Phosphatidylinositol 3 Kinase ◽  
Interleukin 3 ◽  
Survival Signaling ◽  
Phosphatidylinositol 3 ◽  
Constitutively Active

ABSTRACT Two Ras effector pathways leading to the activation of Raf-1 and phosphatidylinositol 3-kinase (PI3K) have been implicated in the survival signaling by the interleukin 3 (IL-3) receptor. Analysis of apoptosis suppression by Raf-1 demonstrated the requirement for mitochondrial translocation of the kinase in this process. This could be achieved either by overexpression of the antiapoptotic protein Bcl-2 or by targeting Raf-1 to the mitochondria via fusion to the mitochondrial protein Mas p70. Mitochondrially active Raf-1 is unable to activate extracellular signal-related kinase 1 (ERK1) and ERK2 but suppresses cell death by inactivating the proapoptotic Bcl-2 family member BAD. However, genetic and biochemical data also have suggested a role for the Raf-1 effector module MEK-ERK in apoptosis suppression. We thus tested for MEK requirement in cell survival signaling using the interleukin 3 (IL-3)-dependent cell line 32D. MEK is essential for survival and growth in the presence of IL-3. Upon growth factor withdrawal the expression of constitutively active MEK1 mutants significantly delays the onset of apoptosis, whereas the presence of a dominant negative mutant accelerates cell death. Survival signaling by MEK most likely results from the activation of ERKs since expression of a constitutively active form of ERK2 was as effective in protecting NIH 3T3 fibroblasts against doxorubicin-induced cell death as oncogenic MEK. The survival effect of activated MEK in 32D cells is achieved by both MEK- and PI3K-dependent mechanisms and results in the activation of PI3K and in the phosphorylation of AKT. MEK and PI3K dependence is also observed in 32D cells protected from apoptosis by oncogenic Raf-1. Additionally, we also could extend these findings to the IL-3-dependent pro-B-cell line BaF3, suggesting that recruitment of MEK is a common mechanism for survival signaling by activated Raf. Requirement for the PI3K effector AKT in this process is further demonstrated by the inhibitory effect of a dominant negative AKT mutant on Raf-1-induced cell survival. Moreover, a constitutively active form of AKT synergizes with Raf-1 in apoptosis suppression. In summary these data strongly suggest a Raf effector pathway for cell survival that is mediated by MEK and AKT.

Polymorphisms of the glucose transporter (GLUT1) gene are associated with diabetic nephropathy

2001 ◽  
Vol 59 (3) ◽  
pp. 985-989 ◽  
Author(s):  
Andrea D. Hodgkinson ◽  
Beverley A. Millward ◽  
Andrew G. Demaine
Keyword(s):  
Diabetic Nephropathy ◽  
Glucose Transporter ◽  
Glucose Transporter Glut1 ◽  
Transporter Glut1 ◽  
Glut1 Gene

scholarly journals Association of phosphatidylinositol 3-kinase with the insulin receptor: compartmentation in rat liver

2000 ◽  
Vol 279 (2) ◽  
pp. E266-E274 ◽  
Author(s):  
Paul G. Drake ◽  
Alejandro Balbis ◽  
Jiong Wu ◽  
John J. M. Bergeron ◽  
Barry I. Posner
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Insulin Receptor ◽  
Rat Liver ◽  
Intracellular Signaling ◽  
Kinase Activity ◽  
Glycogen Synthase ◽  
Metabolic Effects ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Phosphatidylinositol 3-kinase (PI 3-kinase) plays an important role in a variety of hormone and growth factor-mediated intracellular signaling cascades and has been implicated in the regulation of a number of metabolic effects of insulin, including glucose transport and glycogen synthase activation. In the present study we have examined 1) the association of PI 3-kinase with the insulin receptor kinase (IRK) in rat liver and 2) the subcellular distribution of PI 3-kinase-IRK interaction. Insulin treatment promoted a rapid and pronounced recruitment of PI 3-kinase to IRKs located at the plasma membrane, whereas no increase in association with endosomal IRKs was observed. In contrast to IRS-1-associated PI 3-kinase activity, association of PI 3-kinase with the plasma membrane IRK did not augment the specific activity of the lipid kinase. With use of the selective PI 3-kinase inhibitor wortmannin, our data suggest that the cell surface IRK β-subunit is not a substrate for the serine kinase activity of PI 3-kinase. The functional significance for the insulin-stimulated selective recruitment of PI 3-kinase to cell surface IRKs remains to be elucidated.

scholarly journals c-Cbl Is Tyrosine-Phosphorylated by Interleukin-4 and Enhances Mitogenic and Survival Signals of Interleukin-4 Receptor by Linking With the Phosphatidylinositol 3′-Kinase Pathway

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Hiroo Ueno ◽  
Ko Sasaki ◽  
Hiroaki Honda ◽  
Tetsuya Nakamoto ◽  
Tetsuya Yamagata ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Pi3 Kinase ◽  
Interleukin 4 ◽  
Phosphatidylinositol 3 Kinase ◽  
Proliferation And Differentiation ◽  
Interleukin 4 Receptor ◽  
Pi3 Kinase Pathway ◽  
Kinase Pathway ◽  
Phosphatidylinositol 3 ◽  
Survival Signals

Interleukin-4 (IL-4) is a cytokine that induces both proliferation and differentiation and suppresses apoptosis of B cells. Although IL-4 has been shown to activate the phosphatidylinositol 3′ (PI3)-kinase pathway, the role of PI3 kinase in the IL-4 receptor (IL-4R) signaling remains unclear. In this study, we demonstrated that c-Cbl proto-oncogene product is inducibly phosphorylated on tyrosine residues and is associated with the p85 subunit of PI3-kinase by IL-4 stimulation. Overexpression of c-Cbl enhances the PI3-kinase activity and, at the same time, mitogenic activity and survival of cells in the presence of IL-4. However, these effects of c-Cbl were abolished by wortmannin, a specific inhibitor for the PI3 kinase pathway, or by a point mutation at tyrosine 731 of c-Cbl, which is a major binding site for p85. These results indicate that c-Cbl plays a role in linking IL-4R with the PI3 kinase pathway and thus enhancing the mitogenic and survival signals.

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