scholarly journals The Stimulation of pp42mapkinase by Insulin Does Not Correlate with Its Metabolic Actions in Cells Overexpressing Mutant Insulin Receptors

1993 ◽  
Vol 196 (1) ◽  
pp. 301-310 ◽  
Author(s):  
L. Pang ◽  
D.F. Lazar ◽  
D.E. Moller ◽  
J.S. Flier ◽  
A.R. Saltiel
Keyword(s):  
Insulin Receptors ◽  
Mutant Insulin ◽  
Stimulation Of ◽  
In Cells

scholarly journals Insulin activates p21Ras and guanine nucleotide releasing factor in cells expressing wild type and mutant insulin receptors.

1993 ◽  
Vol 268 (27) ◽  
pp. 19998-20001
Author(s):  
B Draznin ◽  
L Chang ◽  
J.W. Leitner ◽  
Y Takata ◽  
J.M. Olefsky
Keyword(s):  
Insulin Receptors ◽  
Guanine Nucleotide ◽  
Wild Type ◽  
Mutant Insulin ◽  
In Cells

Insulin inhibition of protein degradation in cells expressing wild-type and mutant insulin receptors

2003 ◽  
Vol 26 (11) ◽  
pp. 1088-1094 ◽  
Author(s):  
F. G. Hamel ◽  
J. Fawcett ◽  
C. I. Andersen ◽  
P. Berhanu ◽  
R. G. Bennett ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Insulin Receptors ◽  
Wild Type ◽  
Insulin Inhibition ◽  
Mutant Insulin ◽  
In Cells

scholarly journals Signal transduction pathways from insulin receptors to Ras. Analysis by mutant insulin receptors.

1994 ◽  
Vol 269 (6) ◽  
pp. 4634-4640
Author(s):  
K. Yonezawa ◽  
A. Ando ◽  
Y. Kaburagi ◽  
R. Yamamoto-Honda ◽  
T. Kitamura ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Insulin Receptors ◽  
Signal Transduction Pathways ◽  
Mutant Insulin

scholarly journals Involvement of Heat Shock Protein 90 in the Degradation of Mutant Insulin Receptors by the Proteasome

1998 ◽  
Vol 273 (18) ◽  
pp. 11183-11188 ◽  
Author(s):  
Takeshi Imamura ◽  
Tetsuro Haruta ◽  
Yasumitsu Takata ◽  
Isao Usui ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Insulin Receptors ◽  
Heat Shock Protein 90 ◽  
Mutant Insulin

Selective stimulation of Ca2+ flux in cells by maitotoxin

1992 ◽  
Vol 227 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Michio Murata ◽  
Fabian Gusovsky ◽  
Takeshi Yasumoto ◽  
John W. Daly
Keyword(s):  
Selective Stimulation ◽  
Stimulation Of ◽  
In Cells

scholarly journals Insulin receptor substrate 1 rescues insulin action in CHO cells expressing mutant insulin receptors that lack a juxtamembrane NPXY motif.

1995 ◽  
Vol 15 (9) ◽  
pp. 4711-4717 ◽  
Author(s):  
D Chen ◽  
D J Van Horn ◽  
M F White ◽  
J M Backer
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Cho Cells ◽  
Glycogen Synthesis ◽  
Insulin Receptors ◽  
Insulin Receptor Substrate ◽  
Insulin Stimulation ◽  
Insulin Receptor Substrate 1 ◽  
Npxy Motif ◽  
Stimulation Of

Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (IRS-1) and Shc by the activated insulin receptor (IR). Phosphorylation of both proteins is nearly abolished by an alanine substitution at Tyr-960 (A960) in the beta-subunit of the receptor. However, overexpression of IRS-1 in CHO cells expressing the mutant receptor (A960 cells) restored sufficient tyrosine phosphorylation of IRS-1 to rescue IRS-1/Grb-2 binding and phosphatidylinositol 3' kinase activation during insulin stimulation. Shc tyrosine phosphorylation and its binding to Grb-2 were impaired in the A960 cells and were unaffected by overexpression of IRS-1. Although overexpression of IRS-1 increased IRS-1 binding to Grb-2, ERK-1/ERK-2 activation was not rescued. These data suggest that signaling molecules other than IRS-1, perhaps including Shc, are critical for insulin stimulation of p21ras. Interestingly, overexpression of IRS-1 in the A960 cells restored insulin-stimulated mitogenesis and partially restored insulin stimulation of glycogen synthesis. Thus, IRS-1 tyrosine phosphorylation is sufficient to increase the mitogenic response to insulin, whereas insulin stimulation of glycogen synthesis appears to involve other factors. Moreover, IRS-1 phosphorylation is either not sufficient or not involved in insulin stimulation of ERK.

Role of IRS-1-GRB-2 complexes in insulin signaling

1994 ◽  
Vol 14 (6) ◽  
pp. 3577-3587
Author(s):  
M G Myers ◽  
L M Wang ◽  
X J Sun ◽  
Y Zhang ◽  
L Yenush ◽  
...  
Keyword(s):  
Map Kinase ◽  
Insulin Receptor ◽  
Insulin Receptors ◽  
Growth Factor Signaling ◽  
Insulin Stimulation ◽  
Mitogen Activated Protein ◽  
D Cells ◽  
Stimulation Of

GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. Substitution of Tyr-895 with phenylalanine (IRS-1F-895) prevented the IRS-1-GRB-2 association in vivo and in vitro. The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation.

scholarly journals Positive and Negative Regulation of Phosphoinositide 3-Kinase-Dependent Signaling Pathways by Three Different Gene Products of the p85α Regulatory Subunit

2000 ◽  
Vol 20 (21) ◽  
pp. 8035-8046 ◽  
Author(s):  
Kohjiro Ueki ◽  
Petra Algenstaedt ◽  
Franck Mauvais-Jarvis ◽  
C. Ronald Kahn
Keyword(s):  
Glucose Transport ◽  
Kinase Activity ◽  
Glycogen Synthesis ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Regulatory Subunits ◽  
Irs Proteins ◽  
Terminal Structure ◽  
Stimulation Of ◽  
In Cells

ABSTRACT Phosphoinositide (PI) 3-kinase is a key mediator of insulin-dependent metabolic actions, including stimulation of glucose transport and glycogen synthesis. The gene for the p85α regulatory subunit yields three splicing variants, p85α, AS53/p55α, and p50α. All three have (i) a C-terminal structure consisting of two Src homology 2 domains flanking the p110 catalytic subunit-binding domain and (ii) a unique N-terminal region of 304, 34, and 6 amino acids, respectively. To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110α catalytic subunit. PI 3-kinase activity associated with p50α was greater than that associated with p85α or AS53. Increasing the level of p85α or AS53, but not p50α, inhibited both phosphotyrosine-associated and p110-associated PI 3-kinase activities. Expression of a p85α mutant lacking the p110-binding site (Δp85) also inhibited phosphotyrosine-associated PI 3-kinase activity but not p110-associated activity. Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70S6K), was decreased in cells expressing p85α or AS53 but not in cells expressing p50α. Similar inhibition of PI 3-kinase, Akt, and p70S6K was observed, even when p110α was coexpressed with p85α or AS53. Expression of p110α alone dramatically increased glucose transport but decreased glycogen synthase activity. This effect was reduced when p110α was coexpressed with any of the three regulatory subunits. Thus, the three different isoforms of regulatory subunit can relay the signal from IRS proteins to the p110 catalytic subunit with different efficiencies. They also negatively modulate the PI 3-kinase catalytic activity but to different extents, dependent on the unique N-terminal structure of each isoform. These data also suggest the existence of a mechanism by which regulatory subunits modulate the PI 3-kinase-mediated signals, independent of the kinase activity, possibly through subcellular localization of the catalytic subunit or interaction with additional signaling molecules.

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