scholarly journals A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies.

1996 ◽  
Vol 97 (11) ◽  
pp. 2569-2575 ◽  
Author(s):  
K Almind ◽  
G Inoue ◽  
O Pedersen ◽  
C R Kahn
Keyword(s):  
Amino Acid ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Amino Acid Polymorphism ◽  
Insulin Receptor Substrate 1 ◽  
Common Amino Acid ◽  
Impaired Insulin

scholarly journals Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding

2008 ◽  
Vol 8 (1) ◽  
pp. 49-64 ◽  
Author(s):  
Naoto Kubota ◽  
Tetsuya Kubota ◽  
Shinsuke Itoh ◽  
Hiroki Kumagai ◽  
Hideki Kozono ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Hepatic Insulin Signaling

scholarly journals Serine Phosphorylation Proximal to Its Phosphotyrosine Binding Domain Inhibits Insulin Receptor Substrate 1 Function and Promotes Insulin Resistance

2004 ◽  
Vol 24 (21) ◽  
pp. 9668-9681 ◽  
Author(s):  
Yan-Fang Liu ◽  
Avia Herschkovitz ◽  
Sigalit Boura-Halfon ◽  
Denise Ronen ◽  
Keren Paz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Treatment ◽  
Binding Domain ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate ◽  
Control Mechanisms ◽  
Insulin Receptor Substrate 1 ◽  
Phosphotyrosine Binding Domain

ABSTRACT Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-17A), unlike wild-type IRS-1 (IRS-1WT), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-17A to remain complexed with the insulin receptor (IR), unlike IRS-1WT, which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-17A and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.

scholarly journals Reconstitution of Insulin Signaling Pathways in Rat 3Y1 Cells Lacking Insulin Receptor and Insulin Receptor Substrate-1

1998 ◽  
Vol 273 (39) ◽  
pp. 25347-25355 ◽  
Author(s):  
Takanobu Imanaka ◽  
Hideki Hayashi ◽  
Kazuhiro Kishi ◽  
Lihong Wang ◽  
Kazuo Ishii ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Enhancement or inhibition of insulin signaling by insulin receptor substrate 1 is cell context dependent.

1994 ◽  
Vol 14 (7) ◽  
pp. 4427-4434 ◽  
Author(s):  
K Yamauchi ◽  
J E Pessin
Keyword(s):  
Insulin Receptor ◽  
Reporter Gene ◽  
Insulin Signaling ◽  
Transcriptional Activation ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Insulin Receptor Substrate ◽  
Expression Plasmid ◽  
Insulin Receptor Substrate 1 ◽  
Downstream Signaling

Insulin treatment of Chinese hamster ovary (CHO) cells expressing high levels of the insulin receptor (CHO/IR cells) activates both c-fos serum response element and activator protein 1 (AP-1) reporter genes approximately 10-fold. In contrast, parental CHO cells display only two- to threefold insulin stimulation of reporter gene activity. Transient transfection of parental CHO cells with an insulin receptor substrate 1 (IRS1) expression plasmid enhanced insulin downstream signaling in a biphasic manner, whereas IRS1 transfection of CHO/IR cells inhibited insulin signaling in a dose-dependent fashion. Further, expression of Grb2 in parental CHO cells had no effect on insulin signaling, whereas Grb2 increased insulin activation of reporter gene expression in CHO/IR cells. These data suggest that the expression levels of various effector molecules can either enhance or inhibit insulin downstream signaling events. To assess the relative effects of various insulin receptor, IRS1, and Grb2 levels on insulin signaling, parental CHO cells were transiently transfected with various combinations of expression plasmids encoding these proteins. Although expression of IRS1 resulted in a biphasic increase of insulin signaling in parental CHO cells, coexpression of IRS1 with the insulin receptor resulted in inhibition of signaling. This inhibition of insulin signaling directly correlated with an increased association of Grb2 with IRS1 and a concomitant sequestration of Grb2 away from Shc. Consistent with the Shc-Grb2 pathway as the major route for insulin-stimulated c-Fos and AP-1 transcriptional activation, the IRS1-mediated inhibition was reversed by transfection with an expression plasmid for Grb2. These data demonstrate that the extent of insulin-stimulated downstream signaling was dependent not only on the levels of individual signaling molecules but also on the formation of multiprotein complexes with specific stoichiometries.

scholarly journals MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e22839 ◽  
Author(s):  
Dwi Setyowati Karolina ◽  
Arunmozhiarasi Armugam ◽  
Subramaniam Tavintharan ◽  
Michael T. K. Wong ◽  
Su Chi Lim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Phosphorylation of Human Insulin Receptor Substrate-1 at Serine 629 Plays a Positive Role in Insulin Signaling

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4895-4905 ◽  
Author(s):  
Moulun Luo ◽  
Paul Langlais ◽  
Zhengping Yi ◽  
Natalie Lefort ◽  
Elena A. De Filippis ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Human Insulin ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Positive Role ◽  
Human Insulin Receptor
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