Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity

doi:10.1016/0092-8674(89)90098-6

Cell

Volume 58, Issue 4, 25 August 1989, Pages 631-640

https://doi.org/10.1016/0092-8674(89)90098-6 Get rights and content

Abstract

Amino acid sequence of the precursor of the phosphorylated N-glycoprotein (pp63) secreted by rat hepatocytes was deduced from the cDNA sequence. This polypeptide (M_r = 40,586) was rich in both cysteine and proline and contained three potential N-glycosylation sites. A single pp63 mRNA species (∼2000 bp), found in normal hepatocytes but not in FaO hepatoma cells, appeared to result from transcription of a single gene. pp63 purified by affinity chromatography inhibited insulin receptor tyrosine kinase and receptor autophosphorylation. Only the phosphorylated form of the protein was active. In addition, pp63 antagonized the growth-promoting action of insulin in FaO cells but did not affect hormone-mediated increase in amino acid transport capacity or tyrosine aminotransferase induction in these cells.

References (54)

M.M. Bradford
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
(1976)
S. Braun et al.
Synthetic tyrosine polymers as substrates and inhibitors of tyrosine specific protein kinases
J. Biol. Chem.
(1984)
N.L.R. Bucher et al.
Hormonal factors and liver growth
R.L. Cate et al.
Isolation of the bovine and human genes for Mullerian inhibiting substance and expression of the human gene in animal cells
Cell
(1986)
C.K. Chou et al.
Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin
J. Biol. Chem.
(1987)
P. Cohen
Proteolytic events in the post-translational processing of polypeptide hormone precursors
Biochimie
(1987)
J.P. Coughlin et al.
Mullerian inhibiting substance blocks autophosphorylation of EGF receptor by inhibiting tyrosine kinase
Mol. Cell. Endocrinol.
(1987)
T.I. Diamondstone
Assay of tyrosine aminotransferase activity by conversion of p-hydroxyphenylpyruvate to p-hydroxybenzaldehyde
Anal. Biochem.
(1966)
L. Ellis et al.
Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose
Cell
(1986)
B.H. Ginsberg et al.
Insulin-induced dissociation of its receptor into subunits: possible molecular concomitant of negative cooperativity
Biochem. Biophys. Res. Commun.
(1976)

D.M. Hawley et al.

Insulin receptor monoclonal antibodies that mimic insulin action without activating tyrosine kinase

J. Biol. Chem.

(1989)

S.S. Huang et al.

Association of bovine brain derived growth factor receptor with protein tyrosine kinase activity

J. Biol. Chem.

(1986)

S. Jacobs et al.

Somatomedin-C stimulates the phosphorylation of the β-subunit of its own receptor

J. Biol. Chem.

(1983)

N. Josso et al.

The anti-Mullerian hormone

Recent Prog. Horm. Res.

(1977)

D.S. Kelley et al.

Regulation of amino acid transport systems by amino acid depletion and supplementation in monolayer cultures

J. Biol. Chem.

(1978)

A. Le Cam et al.

Secretion of a major phosphorylated glycoprotein by hepatocytes

Characterization of specific antibodies and investigations of the processing, excretion kinetics, and phosphorylation

J. Biol. Chem.

(1985)

J. Massague et al.

The high affinity insulin receptor mediates growth stimulation in rat hepatoma cells

J. Biol. Chem.

(1982)

M.D. Mueckler et al.

Sequences of the precursor to rat ornithine aminotransferase deduced from a cDNA clone

J. Biol. Chem.

(1985)

P.A. Sharp

Speculations on RNA splicing

Cell

(1981)

T.F. Smith et al.

Comparison of biosequences

Adv. Appl. Math.

(1981)

H. Ushiro et al.

Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A431 cell membranes

J. Biol. Chem.

(1980)

M.F. White et al.

A cascade of tyrosine autophosphorylation in the β-subunit activates the insulin receptor

J. Biol. Chem.

(1988)

Y. Zick et al.

The role of antireceptor antibodies in stimulating phosphorylation of the insulin receptor

J. Biol. Chem.

(1984)

J.M. Bishop

Viral oncogenes

Cell

(1985)

N. Blin et al.

Isolation of high molecular weight DNA

Nucl. Acids Res.

(1976)

M. Crettaz et al.

Analysis of insulin action using differentiated and dedifferentiated hepatoma cells

Endocrinology

(1983)

L.G. Davies et al.

Basic Methods in Molecular Biology

Cited by (290)

Impacts of an 8-week regimen of aged garlic extract and aerobic exercise on the levels of Fetuin-A and inflammatory markers in the liver and visceral fat tissue of obese male rats
2023, Clinical Nutrition ESPEN
Obesity-induced chronic low-grade systemic inflammation is linked to the development of numerous diseases. Fetuin-A is known to affect inflammation and insulin resistance in obesity conditions. Free fatty acid (FFA)-induced proinflammatory cytokine expression in adipocytes occurs only in the presence of both Fetuin-A and toll-like receptor 4 (TLR4) and removing either of them prevented FFA-induced insulin resistance. Aged garlic extract (AGE) and exercise training have anti-inflammatory effects; however, the impact of AGE on Fetuin-A is unknown. We examined the effects of AGE with or without aerobic training (AT) on Fetuin-A and inflammatory markers.
Forty healthy male Sprague Dawley rats were randomly assigned to normal diet (ND) (n = 8) or high-fat diet (HFD) groups (n = 32) and fed for 9 weeks. After 9 weeks ND group continued normal diet, and the HFD group was randomly assigned to the HFD, HFD + AGE (600 mg/kg, once daily), HFD + AT (5 days/week), and HFD + AGE + AT groups that were continued for 8 weeks (n = 8). The significance of differences among groups was assessed using one-way analysis of variance followed by the post-hoc Tukey test. Statistically significant differences were considered for p < 0.05.
AGE, AT, and AGE + AT significantly decreased body weight, plasma Fetuin-A, HOMA-IR, mRNA and protein levels of Fetuin-A and NFƙB in the liver and mRNA and Protein levels of Fetuin-A, TLR4 and NFƙB in visceral adipose tissue (VAT) compared to HFD. However, only AGE + AT significantly decreased TLR4 protein levels in the liver.
Although AT and AGE reduce Fetuin-A and inflammatory markers, a combination of the two may be more effective at lowering inflammation.
Pathophysiology of non-alcoholic fatty liver disease (NAFLD)
2023, Medecine des Maladies Metaboliques
Les hépatopathies stéatosiques métaboliques, ou Non alcoholic Fatty Liver Diseases (NAFLD), sont un spectre large de maladies du foie, de la stéatose bénigne, à l’inflammation et à la fibrose. Leur prévalence augmente et en l’absence de traitement, elles représentent un enjeu de recherche et de santé publique. De nombreuses études pré cliniques et cliniques ont permis d’approfondir nos connaissances sur son étiologie et sa physiopathologie, en particulier sur les liens entre NAFLD, obésité et diabète de type 2. Dans cet article, nous faisons une revue des voies métaboliques impliquées dans l’homéostasie des lipides, leur lien avec la sensibilité à l’insuline et leur rôle dans la physiopathologie de la NAFLD.
Non-alcoholic fatty liver diseases (NAFLD) are chronic liver diseases that include simple and benign steatosis, to more severe inflammation and irreversible fibrotic stages. They are the leading chronic liver diseases worldwide and an unmet medical need as there is no treatment and they are major public health issue. Both clinical and pre-clinical studies have provided possible mechanisms underlying NAFLD pathogenesis and its link with obesity and type 2 diabetes. In this article, we review some of the pathways involved in hepatic lipid homeostasis, their sensitivity to insulin signalling and their role in the metabolic origins of NAFLD and its progression.
Friend or foe for obesity: How hepatokines remodel adipose tissues and translational perspective
2023, Genes and Diseases
Due to excess energy intake and a sedentary lifestyle, the prevalence of obesity is rising steadily and has emerged as a global public health problem. Adipose tissue undergoes structural remodeling and dysfunction in the obese state. Secreted proteins derived from the liver, also termed as hepatokines, exert multiple effects on adipose tissue remodeling and the development of obesity, and has drawn extensive attention for their therapeutic potential in the treatment of obesity and related diseases. Several novel hepatokines and their functions on systemic metabolism have been interrogated recently as well. The drug development programs targeting hepatokines also have shown inspiring benefits in obesity treatment. In this review, we outline how adipose tissue changes during obesity. Then, we summarize and critically analyze the novel findings on the effects of metabolic “beneficial” and metabolic “harmful” hepatokines to adipose tissue. We also discuss the in-depth molecular mechanism that hepatokines may mediate the liver-adipose tissue crosstalk, the novel technologies targeting hepatokines and their receptors in vivo to explore their functions, and the potential application of these interventions in clinical practice.
Identification of SNPs and expression patterns of ALB, AHSG and GC genes and their association with growth traits in Hu sheep
2023, Gene
Growth traits are economically important traits in sheep breeding. This study was conducted to evaluate the polymorphisms of ALB, AHSG and GC genes and their association with growth traits in Hu sheep. We measured and recorded the body weight (BW), body height (BH), body length (BL) and feed conversion ratio (FCR) of 1418 male Hu sheep raised in the same environment from 80 to 180 days of age. The total of four SNPs in the ALB, AHSG and GC genes were identified by direct sequencing technology. The results of association analysis showed that two loci (g.8699 A>T and g.13458 T>C) of ALB gene significantly affect average daily gain (ADG; P < 0.05). The genotypes of SNP g.2454 T>C in AHSG gene were significantly associated with ADG and FCR (P < 0.05). There were significant associations between GC g.19484 A>C and BW, BH and BL (P < 0.05). The results of qRT-PCR showed that ALB, AHSG, and GC genes were extremely significantly higher in H_BW sheep compared with those in the L_BW sheep (P < 0.01). These results revealed that ALB-1 g.8699 A>T, ALB-2 g.13458 T>C, AHSG g.2454 T>C and GC g.19484 A>C loci are potential molecular markers for Hu sheep breeding.
The role of hepatokines in NAFLD
2023, Cell Metabolism
Non-alcoholic fatty liver disease (NAFLD) is not only a consequence of insulin resistance, but it is also an important cause of insulin resistance and major non-communicable diseases (NCDs). The close relationship of NAFLD with visceral obesity obscures the role of fatty liver from visceral adiposity as the main pathomechanism of insulin resistance and NCDs. To overcome this limitation, in analogy to the concept of adipokines, in 2008 we introduced the term hepatokines to describe the role of fetuin-A in metabolism. Since then, several other hepatokines were tested for their effects on metabolism. Here we address the dysregulation of hepatokines in people with NAFLD. Then, we discuss pathophysiological mechanisms of cardiometabolic diseases specifically related to NAFLD by focusing on hepatokine-related organ crosstalk. Finally, we propose how the determination of major hepatokines and adipokines can be used for pathomechanism-based clustering of insulin resistance in NAFLD and visceral obesity to better implement precision medicine in clinical practice.
Obesity-mediated insulin resistance in target tissues: role of adiponectin, fetuin-A, and irisin
2023, Metabolic Syndrome: From Mechanisms to Interventions
Insulin resistance is a pathophysiologic hallmark of metabolic syndrome. This chapter highlights the role of adipokines, hepatokines, and myokines in insulin resistance. It begins with insulin resistance in target tissues, primarily adipose tissue, liver, and skeletal muscle. Since the list of secretions from these target tissues is extensive and ever-expanding, this chapter focuses on the emerging functions of three key players namely, adiponectin (an adipokine), fetuin-A (a hepato-adipokine), and irisin (an adipo-myokine), analyzing the significant role essayed by the trio in inter-organ communication deemed crucial in the pathogenesis of insulin resistance. After describing structure and biosynthesis, this chapter elaborates the signaling mechanisms of each of these in target tissues and provides detailed overview of their individual effects. It includes a discussion on inter-organ cross-talk mediated by these proteins and presents schematic representation for easy comprehension. This chapter ends with a note on their consideration as potential biomarkers of insulin resistance.

View all citing articles on Scopus

View full text

Cell

ArticleCharacterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity

Abstract

Anal. Biochem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Biochimie

Mol. Cell. Endocrinol.

Anal. Biochem.

Cell

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Recent Prog. Horm. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Adv. Appl. Math.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Viral oncogenes

Cell

Isolation of high molecular weight DNA

Nucl. Acids Res.

Analysis of insulin action using differentiated and dedifferentiated hepatoma cells

Endocrinology

Basic Methods in Molecular Biology

Article
Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity