| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
(Received for publication, October
31, 1994; and in revised form, January 20, 1995) From the
Recently, we generated mice with a targeted disruption of the
insulin receptor substrate-1 (IRS-1) gene and demonstrated that they
exhibited growth retardation and mild insulin resistance, suggesting
the presence of IRS-1-independent pathway that partially substitutes
for IRS-1 in IRS-1-deficient mice (Tamemoto, H., Kadowaki, T., Tobe,
K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K.,
Kaburagi, Y., Satoh, S., Sekihara, H., Yoshioka, S., Horikoshi, H.,
Furuta, Y., Ikawa, Y., Kasuga, M., Yazaki, Y., and Aizawa, S.(1994) Nature 372, 182-186). We have examined the
[Medline]
insulin-stimulated tyrosine-phosphorylated proteins in livers of wild
type and IRS-1-deficient mice. Tyrosine phosphorylation of an 190-kDa
protein (pp190) by insulin was significantly stimulated in livers of
IRS-1-deficient mice, which was weakly observed in wild type mice in
addition to IRS-1. We also demonstrated that pp190 was immunologically
distinct from IRS-1 and was associated with both the 85-kDa subunit of
phosphatidylinositol 3-kinase and the Grb2/Ash molecule as IRS-1. We
identified pp190 as a novel substrate for insulin receptor kinase
(IRS-2), which can bind both PI3-kinase and Ash/Grb2, and whose
tyrosine phosphorylation is specifically induced in IRS-1-deficient
mice. These data suggested that pp190 may play some physiological roles
in insulin's signal transduction; furthermore, induction of
tyrosine phosphorylation of pp190 may be one of the compensatory
mechanisms that substitute for IRS-1 in IRS-1-deficient mice.
Insulin induces a wide variety of growth and metabolic responses
in many cell types. Insulin initiates its biological effects by
activation of tyrosine kinase in the Among those
substrates, IRS-1 has many tyrosine phosphorylation sites and is
considered to be the platform of signaling complex. Tyrosine
phosphorylation sites in IRS-1 provided binding sites for several
distinct Src homology 2 proteins and may mediate multiple signaling
pathways (Sun et al., 1991; White and Kahn, 1994). Indeed,
IRS-1 binds the 85-kDa subunit of phosphatidylinositol 3-kinase (PI
3-kinase p85) through interaction with Tyr-X-X-Met
motifs, thereby activating PI 3-kinase (Lavan et al., 1992;
Backer et al., 1992; Myers et al., 1992; Folli et
al., 1992). IRS-1 also binds Ash/Grb2 through interaction with
Tyr-Val-Asn-IIe motif when tyrosine-phosphorylated, thereby activating
p21 To better understand
the roles of IRS-1 in normal physiology, we and others generated mice
with a targeted disruption of the IRS-1 gene locus (Tamemoto et
al., 1994; Araki et al., 1994), and we demonstrated that
IRS-1-deficient mice exhibited growth retardation and mild insulin
resistance. These data suggested the existence of a pathway that can
compensate for IRS-1 in IRS-1-deficient mice. In fact, we observed an
insulin-induced increase in both PI 3-kinase activity and MAP kinase
activity in livers of IRS-1-deficient mice (Tamemoto et al.,
1994). These data urged us to examine the insulin-stimulated
tyrosine-phosphorylated proteins in wild type and IRS-1deficient mice.
Here, we report that tyrosine phosphorylation of a 190-kDa protein
(pp190) induced by insulin was significantly increased in
IRS-1-deficient mice. This pp190 was also observed, although less
intensively, in wild type mice. Moreover, we demonstrated that pp190
binds both PI 3-kinase p85 and Ash/Grb2 molecule as IRS-1. These data
suggested that pp190 may play some physiological roles in wild type
mice and, furthermore, the pp190 pathway may serve as one of the
compensatory mechanisms to substitute for IRS-1 in IRS-1-deficient
mice.
Figure 1:
Detection of pp190 in
insulin-injected wild type or IRS-1-deficient mice. Wild type (lanes a-c) or IRS-1-deficient mice (lanes
d-f) were injected without (lanesa and d) or with (lanes b, c, e, and f) insulin via portal veins. At 75 s, livers were removed,
homogenized in buffer A, and centrifuged. The supernatants were
subjected to immunoprecipitation with
In
Figure 2:
PI 3-kinase 85 kDa subunit (p85
We also examined whether pp190 binds Ash/Grb2
molecule. In wild type mice we observed a 160-kDa
tyrosine-phosphorylated protein and a 190-kDa weakly
tyrosine-phosphorylated protein in
Figure 3:
Ash/Grb2 binds tyrosine-phosphorylated
pp190 in wild type or IRS-1-deficient mice. The immunoprecipitates by
Figure 4:
Insulin stimulates PI 3-kinase activity in
We and others generated mice with a targeted disruption of
the IRS-1 gene locus and demonstrated that IRS-1-deficient mice
exhibited growth retardation and mild insulin resistance (Tamemoto et al., 1994; Araki et al., 1994). We also
demonstrated that insulin can significantly stimulate PI 3-kinase
activity and MAP kinase activity, albeit to a lesser extent, in
IRS-1-deficient mice. These data urged us to search for other
substrates that might compensate for the function of IRS-1. In this
study, we have compared the insulin-stimulated tyrosine-phosphorylated
proteins in wild type and IRS-1-deficient mice. We have demonstrated
that tyrosine phosphorylation of an M Our data have shown that tyrosine-phosphorylated pp190
induced by insulin was detectable not only in IRS-1-deficient mice
liver but also in wild type mice liver in Despite the lack of IRS-1, insulin can significantly
stimulate PI 3-kinase and MAP kinase activity in livers of
IRS-1-deficient mice (Tamemoto et al., 1994). Since pp190 is
the only tyrosine-phosphorylated protein detectable in IRS-1-deficient
mice under our conditions, and pp190 seems to have the ability to
couple insulin receptor kinase to a ras p21 pathway via Ash/Grb2-Sos
complex and a PI 3-kinase pathway as IRS-1 does, induction of tyrosine
phosphorylation of pp190 may explain the mechanisms, at least in part,
how deficient IRS-1 was compensated in IRS-1-deficient mice. The
importance of pp190 is further supported by the fact that tyrosine
phosphorylation of pp190 is specifically induced in IRS-1-deficient
mice. Nevertheless, we cannot exclude the possibility that Shc protein,
pp60-like molecule, or 4PS may also contribute to the compensatory
mechanisms, although a significant increase in the degree of
insulin-stimulated tyrosine phosphorylation of Shc protein was not seen
in IRS-1-deficient mice (Tamemoto et al., 1994), nor did we
observe pp60 clearly under our conditions. pp190 and IRS-1 have
several characteristics in common as a substrate for insulin receptor
kinase. First, tyrosine phosphorylation was induced within 30 s after
insulin stimulation(data not shown). Second, both of them are able to
bind PI 3-kinase and Ash/Grb2 simultaneously. Third, they are cytosolic
proteins, which can be extracted without detergent. It may be possible
that they may belong to the same gene family. In this experiment, we
detected pp190 both in wild type and homozygous mice after insulin
stimulation more definitely than previously (Tamemoto et al.,
1994). In our previous report, we homogenized the mice liver in a
boiling homogenization buffer containing SDS. In contrast, we
homogenized the mice liver in an ice-cold homogenization buffer in this
report. It may be advantageous to use the ice-cold buffer without SDS
to detect pp190, pp190 It is of note that 4PS, which was originally found in
IL-3-dependent FDC cell lines as a common substrate for IL-4 receptor
and insulin receptor kinase with a molecular weight similar to that of
IRS-1, is a 170-kDa protein that can bind PI 3-kinase activity (Wang et al., 1993a, 1993b). It is possible that pp190 may in fact
be 4PS. However, pp190 is slightly higher in molecular weight than
IRS-1 (Fig. 1), which has been reported to be similar in size to
4PS (Wang et al., 1993a, 1993b).
Addendum-It seems likely that pp190, which
we demonstrated in this report, is the same molecule as IRS-2, as
reported by Araki et al.(1994).
Volume 270,
Number 11,
Issue of March 17, 1995 pp. 5698-5701
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
-subunit (Kasuga et
al., 1983) and phosphorylates several proteins such as insulin
receptor substrate-1 (IRS-1) (
)(White et al., 1985;
Kadowaki et al., 1987; Tobe et al., 1990), Shc (Pronk et al., 1993; Yonezawa et al., 1994), and pp60
(Momomura et al., 1988). These tyrosine-phosphorylated
substrates bind several Src homology 2 proteins, thereby linking the
tyrosine kinase to activation of cytoplasmic enzymes, which finally
lead to the insulin's biological actions.
leading to the activation of MAP kinase
cascade (Tobe et al., 1993; Skolnik et al., 1993;
Baltensperger et al., 1993; Matuoka et al., 1993).
Moreover, IRS-1 has binding sites for Syp and Nck (Lee et al.,
1993; Kuhne et al., 1993). With regard to other insulin
receptor substrates, the oncoprotein Shc is tyrosine-phosphorylated on
stimulation with insulin and also binds Ash/Grb2 (Pelicci et
al., 1992; Pronk et al., 1993; Yonezawa et al.,
1994). Therefore, IRS-1 and Shc may constitute two major distinct
pathways in the signal transduction of insulin through Ash/Grb2. In
addition, in adipocytes, a 60-kDa protein (pp60) is
tyrosine-phosphorylated by insulin (Momomura et al., 1988).
Recently, pp60 has been shown to bind PI 3-kinase (Lavan et
al., 1993). Another substrate, IL-4-induced phosphotyrosine
substrate (4PS), which is originally found in IL-3-dependent myeloid
cell lines as a common substrate for IL-4 receptor and insulin receptor
kinase and is similar in size to IRS-1, is reported to bind PI 3-kinase
activity (Wang et al., 1993a, 1993b). The signal transduction
of insulin through PI 3-kinase, therefore, may also have two pathways:
IRS-1-dependent and IRS-1independent pathways.
Materials
PI (bovine liver) was purchased from
Avanti Polar Lipids, Inc. Protein G-Sepharose was from Pharmacia
Biotech Inc. [
-
P]ATP (6,000 Ci/mmol) was
from DuPont NEN. Prestained molecular weight markers for sodium dodecyl
sulfate (SDS)-polyacrylamide gel electrophoresis were from Bio-Rad.
Porcine insulin was a gift from Eli Lilly Co. Actrapid human insulin
was from Novo Nordisk A/S (Bagsvaerd, Denmark).Antibodies
The anti-phosphotyrosine antibody
(
PY:PY20) and alkaline-phosphatase-conjugated RC20A were purchased
from Transduction Laboratories. The antibody against the 85-kDa subunit
of PI 3-kinase, AB6, was from MBL (Nagoya, Japan). The antibody against
Ash/Grb2 was from Santa Cruz Biotechnology, Inc. The anti-IRS-1
antibody (IRS-1(1-6)) was a kind gift from Dr. Masaki Nishiyama
(Jikei University School of Medicine, Tokyo) (Furusaka et al.,
1994).Mice
Male mice weighing about 20 g were used in
the studies. Mice were fasted for at least 6 h before the experiment.
The genotypes of the mice used in this experiments were determined as
described (Tamemoto et al., 1994).Immunoprecipitation Followed by Immunoblotting and PI
3-Kinase Assay
Mice were anesthetized by the administration of 2
mg of pentobarbital sodium intraperitoneally 10-15 min before the
experiment. Portal veins were exposed, and 20 units of insulin was
injected via portal veins. At 75 s, livers were removed, homogenized in
ice-cold buffer A (25 mM Tris-HCl, pH 7.4, 10 mM sodium orthovanadate, 10 mM sodium pyrophosphate, 100
mM sodium fluoride, 10 mM EDTA, 10 mM EGTA,
and 1 mM phenylmethylsulfonyl fluoride) and centrifuged. The
supernatants were incubated with PY20, IRS-1(1-6), or
Ash/Grb2, followed by the addition of Protein G-Sepharose. The
immunoprecipitates were washed with 1% Nonidet P-40-buffer A three
times, were subjected to immunoblotting with RC20 followed by the
detection by using an alkaline phosphatase conjugate system (Promega).
The immunoprecipitates with IRS-1(1-6) or Ash/Grb2 were
subjected to PI 3-kinase assay as described previously (Fukui et
al., 1989).
Tyrosine Phosphorylation of pp190 Is Increased in Liver
from Insulin-injected IRS-1-deficient Mice Compared with That in Wild
Type Mice
Wild type or homozygous mice were injected with
insulin via portal veins. 75 seconds after insulin injection, livers
were removed, homogenized, and centrifuged. The supernatants were
subjected to immunoprecipitation with PY followed by
immunoblotting with RC20A. We observed a 160-kDa
tyrosine-phosphorylated protein in liver of insulin-injected wild type
mice (Fig. 1, lane b). This 160-kDa
tyrosine-phosphorylated protein was recognized by an anti-IRS-1
antibody (IRS-1(1-6)) and was thus identified as IRS-1 (Fig. 1, lane c). In addition to IRS-1, we also
observed another weakly tyrosine-phosphorylated protein of 190 kDa,
which was not recognized by IRS-1 (Fig. 1, lanec). In contrast, in homozygous IRS-1-deficient mice, we
observed a 190-kDa tyrosine-phosphorylated protein (pp190) in
insulin-injected mice (Fig. 1, lane e). The 190-kDa
protein was not recognized by IRS-1 (Fig. 1, lane
f). We did not observe a 160-kDa tyrosine-phosphorylated protein
in IRS-1(1-6) immunoprecipitates (Fig. 1, lane f).
Tyrosine phosphorylation of the 190-kDa protein was significantly
increased in insulin-injected IRS-1-deficient mice compared with that
in insulin-injected wild type mice (Fig. 1, lanes b and e). These data suggested that insulin-stimulated tyrosine
phosphorylation of pp190, which was immunologically distinct from
IRS-1, was significantly increased in IRS-1-deficient mice compared
with that in wild type mice. We sometimes observed a 160-kDa protein,
which was not recognized by IRS-1 in insulin-injected
IRS-1-deficient mice (Fig. 1, lane e), although the
detection of this band is not reproducible.
PY (lanesa, b, d, and e) or
IRS-1(1-6) (lanes c and f), followed by Western
blotting with RC20A.
pp190 Is Able to Bind Both PI 3-Kinase p85 and Ash/Grb2
as IRS-1
It has been shown that tyrosine-phosphorylated IRS-1
binds both p85 subunit of PI 3-kinase (p85) and Ash/Grb2 (Tobe et
al., 1993; Skolnik et al., 1993). Therefore, we also
examined whether pp190 binds p85 or Ash/Grb2 as IRS-1 does. The liver
lysates from the wild type or homozygous mice without or with insulin
injection were subjected to immunoprecipitation with p85 or
Ash/Grb2 followed by immunoblotting with RC20A.p85
immunoprecipitates in insulin-injected wild type mice livers, we
observed a 160-kDa tyrosine-phosphorylated protein (Fig. 2, lane b), which is consistent with the previous observation
that PI 3-kinase p85 binds tyrosine-phosphorylated IRS-1. We also
observed a 190-kDa band, although the intensity of the band was weaker (Fig. 2, lane b). In contrast, in insulin-injected
IRS-1-deficient mice, we observed a 190-kDa tyrosine-phosphorylated
protein in p85 immunoprecipitates (Fig. 2, laned). We did not observe a 160-kDa tyrosine-phosphorylated
protein (Fig. 2, laned). The amount of pp190
in p85 immunoprecipitates was increased in IRS-1-deficient mice
compared with that in wild type mice (Fig. 2, lanes b and d).
)
binds tyrosine-phosphorylated pp190 in wild type or IRS-1-deficient
mice. The immunoprecipitates by p85 (AB6) from the liver
lysates of wild type (lanesa and b) or
IRS-1-deficient mice (lanes c and d) without (lanes a and c) or with (lanes b and d) insulin injection were subjected to Western blotting with
RC20A.
Ash/Grb2 immunoprecipitates (Fig. 3, lanesb and e). In contrast,
in IRS-1-deficient mice, we observed a tyrosine-phosphorylated protein
of 190 kDa in Ash/Grb2 immunoprecipitates (Fig. 3, lanes d and f). We did not observe a 160-kDa
tyrosine-phosphorylated protein (Fig. 3, lanes d and f). These data suggested that tyrosine-phosphorylated pp190
binds Ash/Grb2 molecule.
Ash/Grb2 from the liver lysates of wild type (lanes a, b, and e) or IRS-1-deficient mice (lanesc, d, and f) without (lanes a and c) or with insulin injection (lanesb, d, e, and f) were subjected
to Western blotting with RC20A.
pp190 Is Able to Bind Both PI 3-Kinase and Ash/Grb2 in
Simultaneously as IRS-1
Next, to examine whether pp190 is able
to bind p85 and Ash/Grb2 simultaneously, we measured an
insulin-stimulated PI 3-kinase activity in Ash/Grb2
immunoprecipitates in wild type or IRS-1-deficient mice (Fig. 4). In wild type mice, we observed a significant increase
in PI 3kinase activity in Ash/Grb2 immunoprecipitates (Fig. 4, laneb). We also observed a
significant increase in PI 3-kinase activity in insulin-injected
IRS-1-deficient mice (Fig. 4, laned),
suggesting the presence of (a) protein(s) other than IRS-1 which binds
PI 3-kinase activity and Ash/Grb2 simultaneously in an
insulin-dependent manner like IRS-1. While we observed a significant
increase in PI 3-kinase activity in IRS-1(1-6) immunoprecipitates
in wild type mice, we did not observe an insulin-induced increase in PI
3-kinase activity in IRS-1(1-6) immunoprecipitates in
IRS-1-deficient mice (data not shown).
Ash/Grb2 immunoprecipitates in wild type or IRS-1-deficient mice.
The Ash/Grb2 immunoprecipitates from the liver lysates of wild
type (lanesa and b) or IRS-1-deficient mice (lanesc and d) without (lanesa and c) or with (lanesb and d) insulin injection were subjected to PI 3-kinase
assay.
190-kDa
protein was significantly increased in insulin-injected IRS-1-deficient
mice. We also demonstrated that pp190 is able to bind PI 3-kinase p85
and Ash/Grb2 molecule as IRS-1, although they are immuologically
distinct.PY, p85, and
Ash/Grb2 immunoprecipitates. pp190 is not a differently processed
form of IRS-1 gene, since mRNA of IRS-1 was totally absent in
IRS-1-deficient mice. The presence of tyrosinephosphorylated pp190 in
wild type mice suggested that pp190 may have some physiological roles
mediating insulin or insulin-like growth factors' action. It is
possible that the expression of pp190 is essential for the insulin or
insulin-like growth factors' action in some tissues or in certain
stages of development. It is also possible that the expression of IRS-1
and pp190 may be differentially regulated so that these two proteins
have different biological roles. Further study such as the
determination of primary structure of pp190 will be needed to clarify
these points.
p85 complex, and pp190Grb2/Ash
complex.
); MAP kinase, mitogen-activated protein
kinase; Ash, abundant Src homology; Grb2, growth factor receptor-bound
protein 2; IL, interleukin; 4PS, IL-4 phosphotyrosine substrate; IRS-2,
insulin receptor substrate-2; IRS-1, an anti-insulin receptor
substrate-1 antibody; PY, an anti-phosphotyrosine antibody;
p85, an anti-p85 antibody; Ash/Grb2, an anti-Ash/Grb2
antibody.
We thank Dr. Masato Kasuga for helpful discussions and
critical reading of this manuscript. We thank Dr. Masaki Nishiyama
(Jikei University School of Medicine) for the kind gift of an antibody
against IRS-1(1-6). We thank Dr. Kinori Kosaka, Dr. Ryoko Hagura,
Director Hajime Kawashima, and Dr. Osamu Koshio of the Institute for
Diabetes Care and Research, Asahi Life Foundation. We also thank Drs.
Yasushi Kaburagi, Kohjiro Ueki, Yoshihiko Takahashi, Shoji Asai,
Tadashi Yamamoto, Noriko Takahashi, and Ritsuko Yamamoto-Honda for
support.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Kamei, K. Tobe, R. Suzuki, M. Ohsugi, T. Watanabe, N. Kubota, N. Ohtsuka-Kowatari, K. Kumagai, K. Sakamoto, M. Kobayashi, et al. Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissues Causes Macrophage Recruitment and Insulin Resistance J. Biol. Chem., September 8, 2006; 281(36): 26602 - 26614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Saeki, E. Yasugi, E. Okuma, S. N. Breit, M. Nakamura, T. Toda, Y. Kaburagi, and A. Yuo Proteomic analysis on insulin signaling in human hematopoietic cells: identification of CLIC1 and SRp20 as novel downstream effectors of insulin Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E419 - E428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Suzuki, K. Tobe, M. Aoyama, A. Inoue, K. Sakamoto, T. Yamauchi, J. Kamon, N. Kubota, Y. Terauchi, H. Yoshimatsu, et al. Both Insulin Signaling Defects in the Liver and Obesity Contribute to Insulin Resistance and Cause Diabetes in Irs2-/- Mice J. Biol. Chem., June 11, 2004; 279(24): 25039 - 25049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Valverde, D. J. Burks, I. Fabregat, T. L. Fisher, J. Carretero, M. F. White, and M. Benito Molecular Mechanisms of Insulin Resistance in IRS-2-Deficient Hepatocytes Diabetes, September 1, 2003; 52(9): 2239 - 2248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Terauchi, J. Matsui, R. Suzuki, N. Kubota, K. Komeda, S. Aizawa, K. Eto, S. Kimura, R. Nagai, K. Tobe, et al. Impact of Genetic Background and Ablation of Insulin Receptor Substrate (IRS)-3 on IRS-2 Knock-out Mice J. Biol. Chem., April 11, 2003; 278(16): 14284 - 14290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tobe, R. Suzuki, M. Aoyama, T. Yamauchi, J. Kamon, N. Kubota, Y. Terauchi, J. Matsui, Y. Akanuma, S. Kimura, et al. Increased Expression of the Sterol Regulatory Element-binding Protein-1 Gene in Insulin Receptor Substrate-2-/- Mouse Liver J. Biol. Chem., October 12, 2001; 276(42): 38337 - 38340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tsuji, Y. Kaburagi, Y. Terauchi, S. Satoh, N. Kubota, H. Tamemoto, F. B. Kraemer, H. Sekihara, S. Aizawa, Y. Akanuma, et al. Subcellular Localization of Insulin Receptor Substrate Family Proteins Associated With Phosphatidylinositol 3-Kinase Activity and Alterations in Lipolysis in Primary Mouse Adipocytes From IRS-1 Null Mice Diabetes, June 1, 2001; 50(6): 1455 - 1463. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. H. Schacher, R. W. VanHoy, Q. Liu, S. Arkins, R. Dantzer, G. G. Freund, and K. W. Kelley Developmental Expression of Insulin Receptor Substrate-2 During Dimethylsulfoxide-Induced Differentiation of Human HL-60 Cells J. Immunol., January 1, 2000; 164(1): 113 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-H. Qu, M. Karas, A. Koval, and D. LeRoith Insulin Receptor Substrate-4 Enhances Insulin-like Growth Factor-I-induced Cell Proliferation J. Biol. Chem., October 29, 1999; 274(44): 31179 - 31184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Auclair, C. Vigouroux, C. Desbois-Mouthon, J. Deibener, P. Kaminski, O. Lascols, G. Cherqui, J. Capeau, and M. Caron Antiinsulin Receptor Autoantibodies Induce Insulin Receptors to Constitutively Associate with Insulin Receptor Substrate-1 and -2 and Cause Severe Cell Resistance to Both Insulin and Insulin-Like Growth Factor I J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3197 - 3206. [Abstract] [Full Text]
|
|
|
|
|
|
S. C. H. Liu, Q. Wang, G. E. Lienhard, and S. R. Keller Insulin Receptor Substrate 3 Is Not Essential for Growth or Glucose Homeostasis J. Biol. Chem., June 18, 1999; 274(25): 18093 - 18099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. del Aguila, K. P. Claffey, and J. P. Kirwan TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells Am J Physiol Endocrinol Metab, May 1, 1999; 276(5): E849 - E855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Miele, M. Caruso, V. Calleja, R. Auricchio, F. Oriente, P. Formisano, G. Condorelli, A. Cafieri, D. Sawka-Verhelle, E. Van Obberghen, et al. Differential Role of Insulin Receptor Substrate (IRS)-1 and IRS-2 in L6 Skeletal Muscle Cells Expressing the Arg1152 right-arrow Gln Insulin Receptor J. Biol. Chem., January 29, 1999; 274(5): 3094 - 3102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-O. Contreres, R. Faure, G. Baquiran, J. J. Bergeron, and B. I. Posner ATP-dependent Desensitization of Insulin Binding and Tyrosine Kinase Activity of the Insulin Receptor Kinase. THE ROLE OF ENDOSOMAL ACIDIFICATION J. Biol. Chem., August 21, 1998; 273(34): 22007 - 22013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ohan, M. Bayaa, P. Kumar, L. Zhu, and X. J. Liu A Novel Insulin Receptor Substrate Protein, xIRS-u, Potentiates Insulin Signaling: Functional Importance of Its Pleckstrin Homology Domain Mol. Endocrinol., August 1, 1998; 12(8): 1086 - 1098. [Abstract] [Full Text]
|
|
|
|
|
|
P. M. Sharma, K. Egawa, Y. Huang, J. L. Martin, I. Huvar, G. R. Boss, and J. M. Olefsky Inhibition of Phosphatidylinositol 3-Kinase Activity by Adenovirus-mediated Gene Transfer and Its Effect on Insulin Action J. Biol. Chem., July 17, 1998; 273(29): 18528 - 18537. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamauchi, Y. Kaburagi, K. Ueki, Y. Tsuji, G. R. Stark, I. M. Kerr, T. Tsushima, Y. Akanuma, I. Komuro, K. Tobe, et al. Growth Hormone and Prolactin Stimulate Tyrosine Phosphorylation of Insulin Receptor Substrate-1, -2, and -3, Their Association with p85 Phosphatidylinositol 3-Kinase (PI3-kinase), and Concomitantly PI3-kinase Activation via JAK2 Kinase J. Biol. Chem., June 19, 1998; 273(25): 15719 - 15726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Richards, M. P. Walker, J. Sebastian, and R. P. DiAugustine Insulin-like Growth Factor-1 (IGF-1) Receptor-Insulin Receptor Substrate Complexes in the Uterus. ALTERED SIGNALING RESPONSE TO ESTRADIOL IN THE IGF-1m/m MOUSE J. Biol. Chem., May 8, 1998; 273(19): 11962 - 11969. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Valverde, M. Lorenzo, S. Pons, M. F. White, and M. Benito Insulin Receptor Substrate (IRS) Proteins IRS-1 and IRS-2 Differential Signaling in the Insulin/Insulin-Like Growth Factor-I Pathways in Fetal Brown Adipocytes Mol. Endocrinol., May 1, 1998; 12(5): 688 - 697. [Abstract] [Full Text]
|
|
|
|
|
|
C. J. Band, B. I. Posner, V. Dumas, and J.-O. Contreres Early Signaling Events Triggered by Peroxovanadium [bpV(phen)] Are Insulin Receptor Kinase (IRK)-Dependent: Specificity of Inhibition of IRK-Associated Protein Tyrosine Phosphatase(s) by bpV(phen) Mol. Endocrinol., December 1, 1997; 11(13): 1899 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kaburagi, S. Satoh, H. Tamemoto, R. Yamamoto-Honda, K. Tobe, K. Veki, T. Yamauchi, E. Kono-Sugita, H. Sekihara, S. Aizawa, et al. Role of Insulin Receptor Substrate-1 and pp60 in the Regulation of Insulin-induced Glucose Transport and GLUT4 Translocation in Primary Adipocytes J. Biol. Chem., October 10, 1997; 272(41): 25839 - 25844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Haddad and C. A. Conover Insulin and Interleukin-4 Induce Desensitization to the Mitogenic Effects of Insulin-like Growth Factor-I. PIVOTAL ROLE FOR INSULIN RECEPTOR SUBSTRATE-2 J. Biol. Chem., August 1, 1997; 272(31): 19525 - 19531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Rondinone, L.-M. Wang, P. Lonnroth, C. Wesslau, J. H. Pierce, and U. Smith Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus PNAS, April 15, 1997; 94(8): 4171 - 4175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Argetsinger, G. Norstedt, N. Billestrup, M. F. White, and C. Carter-Su Growth Hormone, Interferon-gamma , and Leukemia Inhibitory Factor Utilize Insulin Receptor Substrate-2 in Intracellular Signaling J. Biol. Chem., November 15, 1996; 271(46): 29415 - 29421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wery, M. Letourneur, J. Bertoglio, and J. Pierre Interleukin-4 Induces Activation of Mitogen-activated Protein Kinase and Phosphorylation of Shc in Human Keratinocytes J. Biol. Chem., April 12, 1996; 271(15): 8529 - 8532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Krook, D. E. Moller, K. Dib, and S. O'Rahilly Two Naturally Occurring Mutant Insulin Receptors Phosphorylate Insulin Receptor Substrate-1 (IRS-1) but Fail to Mediate the Biological Effects of Insulin J. Biol. Chem., March 22, 1996; 271(12): 7134 - 7140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kong, C. Mounier, J. Wu, and B. I. Posner Epidermal Growth Factor-induced Phosphatidylinositol 3-Kinase Activation and DNA Synthesis. IDENTIFICATION OF Grb2-ASSOCIATED BINDER 2 AS THE MAJOR MEDIATOR IN RAT HEPATOCYTES J. Biol. Chem., November 10, 2000; 275(46): 36035 - 36042. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
