Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC‐1 in dermal fibroblasts from patients with syndromes of severe insulin resistance

Whitehead, J. P.; Humphreys, P; Dib, Karim; Goding, James W.; O’Rahilly, Stephen

doi:10.1046/j.1365-2265.1997.2171021.x

Cited by 14 publications

(11 citation statements)

References 13 publications

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“…Conversely, PC-1 expression is reduced in cells with severe forms of insulin resistance due to receptor or postreceptor downstream genetic defects (30). Taken together, these data indicate that PC-1, rather than simply being an inhibitor of insulin action, is likely to be a fine tuner of the modulation of the insulin receptor.…”

Section: Discussionmentioning

confidence: 47%

Insulin modulates PC-1 processing and recruitment in cultured human cells

Menzaghi

Paola

Baj³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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We evaluated whether insulin signaling modulates plasma cell glycoprotein (PC-1) plasma membrane recruitment, posttranslational processing, and gene expression in human cultured cell lines. Insulin induced a fourfold increase ( P < 0.01) of membrane PC-1 expression by rapid and sensitive mechanism(s). This effect was reduced ( P < 0.05–0.01) by inhibition of phosphatidylinositol 3-kinase (200 nmol/l wortmannin) and S6 kinase (50 nmol/l rapamycin) activities and intracellular trafficking (50 μmol/l monensin) and was not accompanied by PC-1 gene expression changes. Moreover, at Western blot, insulin elicited the appearance, in both plasma membrane and cytosol, of a PC-1-related 146-kDa band (in addition to bands of 163, 117, 106, and 97 kDa observed also in absence of insulin) that was sensitive to endoglycosidase H. Finally, inhibition of PC-1 translocation to plasma membrane, by wortmannin pretreatment, increases insulin-stimulated receptor autophosphorylation. Our data indicate that insulin stimulates PC-1 posttranslational processing and translocation to the plasma membrane, which in turn impairs insulin receptor signaling. Bidirectional cross talk between insulin and PC-1, therefore, takes place, which may be part of the hormone self-desensitization mechanism.

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Section: Discussionmentioning

confidence: 47%

Insulin modulates PC-1 processing and recruitment in cultured human cells

Menzaghi

Paola

Baj³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…G o l d fine and colleagues (21)(22)(23)(24) reported several studies showing the association of high PC-1 expression with defective insulin action in human tissues. However, Whitehead et al (30) reported no increase in PC-1 expression level in dermal fibroblasts from patients with syndromes of insulin resistance. In addition, it was shown that PC-1 is markedly (~10-fold) overexpressed in the tissues as well as cultured skin fibroblasts from the patients of Lowe's syndrome (31).…”

Section: Discussionmentioning

confidence: 97%

No correlation of plasma cell 1 overexpression with insulin resistance in diabetic rats and 3T3-L1 adipocytes.

et al. 1999

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Membrane glycoprotein plasma cell 1 (PC-1) has been shown to be increased in type 2 diabetes and involved in insulin resistance through inhibiting the insulin receptor tyrosine kinase, which was demonstrated using cultured breast cancer cells. However, other reports have shown contradictory results in Chinese hamster ovary cells and in vitro kinase assay. Thus, we considered it necessary to investigate the effect of PC-1 using highly insulin-sensitive cells. Here, we used two of the following approaches: 1) investigating PC-1 expression levels in insulin-responsive tissues in rat models of diabetes and 2) overexpressing PC-1 in 3T3-L1 adipocytes. We found that PC-1 was highly expressed in insulin-responsive tissues, such as liver and adipose tissue, in normal rats. However, high-fat feeding or streptozotocin-induced diabetes did not change its expression levels in liver, adipose tissue, and skeletal muscle. Thus, PC-1 expression levels were not associated with high-fat-diet-induced insulin resistance or hyperglycemia. Although PC-1 was increased in adipose tissue in Zucker fatty rats (protein level, by 50%; mRNA level, by 90%), its expression levels in liver and skeletal muscle, tissues that are more responsible for whole body glucose metabolism than adipose tissue, did not significantly differ from those in normal rats. Next, we overexpressed PC-1 in 3T3-L1 adipocytes using an adenovirus transfection system. PC-1 expression was markedly increased to a level 16-fold greater than that in normal human adipose tissue, which is higher than the previously reported levels in diabetic patients. However, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate 1, activation of phosphatidylinositol 3-kinase, and glucose uptake were not affected by PC-1 overexpression. These results strongly suggest that increased PC-1 expression is not causally related to insulin resistance.

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“…However, the role of PC-1, if any, in insulin resistance has been highly controversial [81][82][83]. It has been suggested that the inhibition of phosphorylation of the insulin receptor by PC-1 is an in vitro artifact due to destruction of ATP [81], but this mechanism obviously cannot apply in the case where the enzymic activity of PC-1 has been abolished by mutagenesis of the active site threonine [80].…”

Section: Pc-1 and Insulin Resistancementioning

confidence: 98%

Ecto-enzymes: physiology meets pathology

Goding

2000

Journal of Leukocyte Biology

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101

111

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Ecto-enzymes are catalytic membrane proteins with their active sites outside the cell. They include cholinesterase, which inactivates acetylcholine, and angiotensin-converting enzyme, which converts angiotensin I to biologically active angiotensin II, and numerous other peptidases, transpeptidases, nucleotidases, phosphodiesterases, and phosphatases. Many CD antigens of leukocytes are ecto-enzymes; some CD antigens for which no function is currently known are probably ectoenzymes. Expression is highly regulated and correlated with differentiation and activation. Some are highly restricted in distribution; others are ubiquitous. Many are shared between leukocytes and non-hematogenous cells. Biological functions appear to depend on the type and location of the cell in which expression occurs, and include recycling of nutrients, local control of response to cytokines and hormones, bone formation, cell mobility, invasion, and metastasis. Many novel regulatory functions of ecto-enzymes remain to be discovered, and may reveal new mechanisms of local extracellular control of cellular function.

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Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC‐1 in dermal fibroblasts from patients with syndromes of severe insulin resistance

Cited by 14 publications

References 13 publications

Insulin modulates PC-1 processing and recruitment in cultured human cells

Insulin modulates PC-1 processing and recruitment in cultured human cells

No correlation of plasma cell 1 overexpression with insulin resistance in diabetic rats and 3T3-L1 adipocytes.

Ecto-enzymes: physiology meets pathology

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