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

Auberger, Patrick; Falquerho, Laurence; Contreres, Jean Olivier; Pagès, Gilles; Cam, Ginette Le; Rossi, Bernard; Cam, Alphonse Le

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

Cited by 303 publications

(248 citation statements)

References 45 publications

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“…As yet, the fetuin family encompasses a series of tightly related proteins that are synthesized mostly in the liver and have been variably designated fetuin in sheep, pig and cow, α2-HS-glycoprotein (AHSG) in human, phosphoprotein of 63 kDa (pp63) in rat, or countertrypin in mouse and gerbil [2][3][4][5][6][7]. In fact, their close sequence similarities indicate that fetuin, AHSG, pp63 and countertrypin all originate from a single ancestral gene and are counterparts of a single protein, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…AHSG modulates some insulin-driven and kinase-mediated signal-transduction pathways, possibly in a tissue-specific fashion [16]. AHSG\pp63 inhibits the insulin receptor autophosphorylation mediated by its intrinsic tyrosine kinase activity [5] and the phosphorylation status of AHSG\pp63 is in turn of critical importance for its tyrosine kinase inhibitory activity [5,17,18]. Furthermore, the phosphorylated form of pp63 inhibits the binding of hepatocyte growth factor to its hepatic receptor [19].…”

Section: Introductionmentioning

confidence: 99%

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Fetuin-B, a second member of the fetuin family in mammals

Olivier

Soury

Ruminy

et al. 2000

Biochemical Journal

111

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A set of orthologous plasma proteins found in human, sheep, pig, cow and rodents, now collectively designated fetuin-A, constitutes the fetuin family. Fetuin-A has been identified as a major protein during fetal life and is also involved in important functions such as inhibition of the insulin receptor tyrosine kinase activity, protease inhibitory activities and development-associated regulation of calcium metabolism and osteogenesis. Furthermore, fetuin-A is a key partner in the recovery phase of an acute inflammatory response. We now describe a second protein of the fetuin family, called fetuin-B, which is found at least in human and rodents. On grounds of domain homology, overall conservation of cysteine residues and chromosomal assignments of the corresponding genes in these species, fetuin-B is unambiguously a paralogue of fetuin-A. Yet, fetuin-A and fetuin-B exhibit significant differences at the amino acid sequence level, notably including variations with respect to the archetypal fetuin-specific signature. Differences and similarities in terms of gene regulation were also observed. Indeed, studies performed during development in rat and mouse showed for the first time high expression of a member of the fetuin family in adulthood, as shown with the fetuin-B mRNA in rat. However, like its fetuin-A counterpart, the fetuin-B mRNA level is down-regulated during the acute phase of experimentally induced inflammation in rat.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fetuin-B, a second member of the fetuin family in mammals

Olivier

Soury

Ruminy

et al. 2000

Biochemical Journal

111

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“…Fetuin, abundant in fetal calf serum, is the equivalent protein in other species (Dziegielewska et al 1990). AHSG\fetuin is a multi-functional protein with an inhibitory effect on insulin receptor tyrosine kinase as a phosphorylation substrate (Auberger et al 1989). AHSG\fetuin binds Ca# + with high affinity, thereby preventing apatite formation in the circulation, and it is concentrated in the extra-cellular matrix of the bone marrow (JahnenDechent et al 1997).…”

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confidence: 99%

Haplotype analysis of the human α2‐HS glycoprotein (fetuin) gene

Osawa

Yuasa

Kitano

et al. 2001

Annals of Human Genetics

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Alpha2-HS glycoprotein (AHSG), which is equivalent to fetuin in other species, is a protein found in human plasma. AHSG is polymorphic with two common alleles and many variants. To examine the intragenic haplotypes and their diversity at this locus, a contiguous genomic DNA sequence (10n3 kb) was analyzed in 20 samples (40 chromosomes), and haplotypes were determined for 309 subjects. Judging from the aligned nucleotide sequences and the conserved amino acid residues comparing human and chimpanzee AHSG, it was concluded that the type 1 allele is probably older and has evolved into four major suballeles. The type 2 allele was generated from one branch of the type 1 allele. AHSG*3 and *5 variants were each found to have a single nucleotide change in exon 7, resulting in the change of an amino acid residue from Arg #** to Cys and from Asp #&) to Asn, respectively. It was noted that the AHSG*3 mutation gives rise to an additional cysteine residue, which possibly affects the conformation of the protein. The AHSG gene was found to have a low mutation rate and no apparent recombination events. Furthermore, the detected substitutions were nonhomogeneously distributed at this locus. In particular, four nonsynonymous substitutions were concentrated in the carboxyl-terminal domain. Alpha2-HS glycoprotein (AHSG) is a 46 kDa plasma protein mainly synthesized by hepatocytes. The molecule consists of two polypeptide chains produced through post-translational cleavage from a single polypeptide by enzymatic proteolysis ; the two chains are linked by a disulfide bond (Lee et al. 1987 ;Nawratil et al. 1996). AHSG is a member of the cystatin superfamily which includes kininogen and

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“…Serine phosphorylation was shown to be critically required for rat fetuin inhibition of the insulin receptor tyrosine kinase (29) and multiple serine phosphorylation was also demonstrated in human fetuin (38). In contrast, the inhibition of apatite formation by fetuins was largely independent of secondary amino acid modifications (18).…”

Section: Discussionmentioning

confidence: 99%

“…Bovine fetuin has been implicated in the stimulation of cell growth (27) and the modulation of brain development (28). The rat homologue, first described as phosphoprotein pp63, was shown to be an inhibitor of the endogenous tyrosine kinase activity associated with the insulin receptor (29,30). The fetuins have therefore been implicated in the regulation of the mitogenic response following insulin stimulation (29 -31).…”

Section: Discussionmentioning

confidence: 99%

Limited Proteolysis of Human α2-HS Glycoprotein/Fetuin

Nawratil¹,

Lenzen²,

Kellermann

et al. 1996

Journal of Biological Chemistry

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␣ 2 -HS glycoprotein is a major protein of human plasma whose function is still obscure. A proteolytically processed form of ␣ 2 -HS glycoprotein lacking a segment of 40 amino acid residues bridging its heavy and light chain portions ("connecting peptide") has been described suggesting that this peptide is released by posttranslational processing to fulfill biological role(s) of ␣ 2 -HS glycoprotein. To test this hypothesis we investigated how the connecting peptide is released from the parental molecule by limited proteolysis. We developed monoclonal antibodies to various portions of the connecting peptide and its NH 2 -terminal flanking region which cross-react with the native ␣ 2 -HS glycoprotein. Purified ␣ 2 -HS glycoprotein from human plasma was subjected to limited proteolysis by proteinases including trypsin, chymotrypsin, elastase plasmin, kallikrein, thrombin, and renin. Immunoprint analysis of the proteolytic digests indicated that ␣ 2 -HS glycoprotein is readily cleaved in its connecting peptide region. NH 2 -terminal amino sequence analysis of the generated fragments demonstrated that a single proteinase, chymotrypsin, cleaves the critical Leu-Leu bond flanking the NH 2 -terminal portion of the connecting peptide region. Most but not all of the other proteinase cleavage sites map to a short stretch of 9 residues located in the center portion of the connecting peptide region. Immunoprint analysis of plasma samples from patients with sepsis demonstrate that the connecting peptide region is cleaved under pathological conditions. Our results indicate that the connecting peptide and/or fragments thereof are readily releasable from ␣ 2 -HS glycoprotein in vitro and in vivo.Human ␣ 2 -HS glycoprotein (␣ 2 -HS) 1 belongs to the fetuin family of proteins that are collectively named after the bovine species homologue, fetuin (1). Fetuins are glycoproteins with both N-linked and O-linked carbohydrate side chains (2, 3).Fetuins occur in large amounts in blood and cerebrospinal fluid and accumulate to high concentrations in calcified bone (4). The fetuins form a family within the superfamily of mammalian cystatins (5); they are characterized by a tripartite structure, i.e. two NH 2 -terminally located cystatin-like domains (D1, D2) and a unique COOH-terminal domain (D3) not present in other mammalian cystatins (6). Although many biological functions have been attributed to fetuins, none has been unequivocally established to date (for review, see Ref. 7).The human homologue of fetuin, ␣ 2 -HS glycoprotein, has long been known as a major protein of the plasma and the cerebrospinal fluid. Early studies have demonstrated that ␣ 2 -HS isolated from Cohn's fraction VI of human plasma is a two-chain molecule consisting of a A-chain of 282 amino acid residues and a B-chain of 27 residues (8, 9). Cloning of the ␣ 2 -HS cDNA revealed that a single mRNA transcript encodes the A and the B chains, and that a sequence segment of 40 residues ("connecting peptide") bridges the A and B portions in the primary translation product...

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

Cited by 303 publications

References 45 publications

Fetuin-B, a second member of the fetuin family in mammals

Fetuin-B, a second member of the fetuin family in mammals

Haplotype analysis of the human α2‐HS glycoprotein (fetuin) gene

Limited Proteolysis of Human α2-HS Glycoprotein/Fetuin

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