scholarly journals A carboxy-terminal truncated insulin receptor substrate-1 dominant negative protein reverses the human hepatocellular carcinoma malignant phenotype.

1996 ◽  
Vol 98 (9) ◽  
pp. 2100-2108 ◽  
Author(s):  
S Tanaka ◽  
J R Wands
Keyword(s):  
Hepatocellular Carcinoma ◽  
Insulin Receptor ◽  
Human Hepatocellular Carcinoma ◽  
Dominant Negative ◽  
Insulin Receptor Substrate ◽  
Malignant Phenotype ◽  
Insulin Receptor Substrate 1 ◽  
Carboxy Terminal

scholarly journals The Pleckstrin Homology (PH) Domain-Interacting Protein Couples the Insulin Receptor Substrate 1 PH Domain to Insulin Signaling Pathways Leading to Mitogenesis and GLUT4 Translocation

2002 ◽  
Vol 22 (20) ◽  
pp. 7325-7336 ◽  
Author(s):  
Janet Farhang-Fallah ◽  
Varinder K. Randhawa ◽  
Anjaruwee Nimnual ◽  
Amira Klip ◽  
Dafna Bar-Sagi ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Insulin Receptor ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Insulin Receptor Substrate ◽  
Glut4 Translocation ◽  
Ph Domain ◽  
Insulin Receptor Substrate 1 ◽  
Interacting Protein ◽  
Negative Mutant

ABSTRACT Receptor-mediated tyrosine phosphorylation of the insulin receptor substrate 1 (IRS-1) is required for the propagation of many of insulin's biological effects. The amino-terminal pleckstrin homology (PH) domain of IRS-1 plays a pivotal role in promoting insulin receptor (IR)-IRS-1 protein interactions. We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner. In contrast, a dominant-negative mutant of PHIP (DN-PHIP) was shown to specifically block transcriptional and mitogenic signals elicited by insulin and not serum. In order to examine whether PHIP/IRS-1 complexes participate in the signal transduction pathway linking the IR to GLUT4 traffic in muscle cells, L6 myoblasts stably expressing a myc-tagged GLUT4 construct (L6GLUT4myc) were transfected with either wild-type or dominant-interfering forms of PHIP. Whereas insulin-dependent GLUT4myc membrane translocation was not affected by overexpression of PHIP, DN-PHIP caused a nearly complete inhibition of GLUT4 translocation, in a manner identical to that observed with a dominant-negative mutant of the p85 subunit of phosphatidylinositol 3-kinase (Δp85). Furthermore, DN-PHIP markedly inhibited insulin-stimulated actin cytoskeletal reorganization, a process required for the productive incorporation of GLUT4 vesicles at the cell surface in L6 cells. Our results are consistent with the hypothesis that PHIP represents a physiological protein ligand of the IRS-1 PH domain, which plays an important role in insulin receptor-mediated mitogenic and metabolic signal transduction.

scholarly journals Expression and Significance of Insulin Receptor Substrate 1 in Human Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Chun Gao ◽  
Hui Zhang ◽  
Wei-Shuo Zhang ◽  
Long Fang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Insulin Receptor ◽  
Signal Transduction Pathway ◽  
Binary Logistic Regression ◽  
Insulin Receptor Substrate ◽  
Binary Logistic Regression Model ◽  
Insulin Receptor Substrate 1 ◽  
Insulin Signal Transduction ◽  
Positive Expression ◽  
Insulin Signal Transduction Pathway

Background. Insulin receptor substrate 1 (IRS-1) is an important molecule of the insulin signal transduction pathway and has been associated with the occurrence and development of many tumors, including hepatocellular carcinoma (HCC). Our study was designed to determine the expression and significance of IRS-1 in human HCC. Methods. Two hundred and forty specimens were drawn from 140 patients, including 100 HCC tissues and 100 paracancerous (PC) tissues from 100 HCC patients, 20 liver cirrhosis (LC) tissues from 20 LC patients, and 20 chronic hepatitis (CH) tissues from 20 CH patients. Baseline and pathological characteristics were included, and the expression of IRS-1 was examined by immunohistochemical (IHC) staining. Binary logistic regression model calculation was used for multivariate analysis. Results. The total positive rates of IRS-1 expression were 41.0%, 17.0%, 15.0%, and 10.0% in HCC, PC, LC and CH tissues, respectively. IRS-1-positive signals were brown in color and located in the nucleus and cytoplasm. Compared with PC, LC, and CH tissues, a significantly increased expression was observed in human HCC tissues (P<0.001, P=0.028, and P=0.008). Eight of the total 240 specimens had the strong immunostaining of IRS-1 expression, and all of them were HCC tissues. After control of the age, gender, and HBV and HCV infection, IRS-1 expression was independently associated with the diagnosis of HCC (OR 6.60, 95% CI 2.243-19.425, P=0.001). Conclusions. Positive expression of IRS-1 in HCC was increased significantly and may play an important role in the occurrence and development of human HCC.

scholarly journals Association between GRB2/Sos and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: implications for Ras activation by insulin.

1995 ◽  
Vol 15 (3) ◽  
pp. 1778-1785 ◽  
Author(s):  
W Pruett ◽  
Y Yuan ◽  
E Rose ◽  
A G Batzer ◽  
N Harada ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Cell Line ◽  
Tyrosine Phosphorylation ◽  
Dominant Negative ◽  
Interleukin 4 ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Erk Activation ◽  
Ras Activation ◽  
Extracellular Signal

Insulin receptor substrate 1 (IRS-1) mediates the activation of a variety of signaling pathways by the insulin and insulin-like growth factor 1 receptors by serving as a docking protein for signaling molecules with SH2 domains. We and others have shown that in response to insulin stimulation IRS-1 binds GRB2/Sos and have proposed that this interaction is important in mediating Ras activation by the insulin receptor. Recently, it has been shown that the interleukin (IL)-4 receptor also phosphorylates IRS-1 and an IRS-1-related molecule, 4PS. Unlike insulin, however, IL-4 fails to activate Ras, extracellular signal-regulated kinases (ERKs), or mitogen-activated protein kinases. We have reconstituted the IL-4 receptor into an insulin-responsive L6 myoblast cell line and have shown that IRS-1 is tyrosine phosphorylated to similar degrees in response to insulin and IL-4 stimulation in this cell line. In agreement with previous findings, IL-4 failed to activate the ERKs in this cell line or to stimulate DNA synthesis, whereas the same responses were activated by insulin. Surprisingly, IL-4's failure to activate ERKs was not due to a failure to stimulate the association of tyrosine-phosphorylated IRS-1 with GRB2/Sos; the amounts of GRB2/Sos associated with IRS-1 were similar in insulin- and IL-4-stimulated cells. Moreover, the amounts of phosphatidylinositol 3-kinase activity associated with IRS-1 were similar in insulin- and IL-4-stimulated cells. In contrast to insulin, however, IL-4 failed to induce tyrosine phosphorylation of Shc or association of Shc with GRB2. Thus, ERK activation correlates with Shc tyrosine phosphorylation and formation of an Shc/GRB2 complex. Thus, ERK activation correlates with Shc tyrosine phosphorylation and formation of an Shc/GRB2 complex. Previous studies have indicated that activation of ERks in this cell line is dependent upon Ras since a dominant-negative Ras (Asn-17) blocks ERK activation by insulin. Our findings, taken in the context of previous work, suggest that binding of GRB2/Sos to Shc may be the predominant mechanism whereby insulin as well as cytokine receptors activate Ras.

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