Demonstration of Type I Insulin-Like Growth Factor Receptors on Human Platelets

Hartmann, K.; Baier, Thomas; Loibl, R; Schmitt, Andreas; Schönberg, D

doi:10.3109/10799898909066053

Cited by 19 publications

(14 citation statements)

References 27 publications

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Section: Discussionmentioning

confidence: 99%

“…Even though platelets have been demonstrated to express the IGF receptor on their plasma membrane as early as 1989, 24 their functional role and the signaling mechanisms that are stimulated by IGF-1 are still largely unknown. One of the first events after IGF stimulation of cells is autophosphorylation of the ␤ subunits on tyrosine residues, leading to activation of its kinase activity and phosphorylation of downstream substrates.…”

Section: Igf-1 Stimulates Rapid Phosphorylation Of the Igf Receptor Omentioning

confidence: 99%

“…23 They express high levels of the IGF-1 receptor on their plasma membrane, 24 and local increases in free IGF-1 concentrations may therefore play an important role in the autocrine and paracrine regulation of platelet function. To obtain an insight into the role of IGF-1 in hemostasis and pathologic conditions such as cardiovascular disease, it is essential to delineate the physiologic role of IGF-1 and the intracellular signaling pathways that are involved in its modulation of platelet function.…”

Section: Introductionmentioning

confidence: 99%

“…Platelets indeed express high levels of the IGF receptor on their plasma membrane. 24 Changes in the levels of IGF-1-binding proteins and increased local concentrations of IGF-1, further contributed to by secretion of IGF-1 from the ␣ granules, 4,5 may therefore positively regulate platelet function and contribute to cardiovascular disease.Although a single report had previously shown IGF-1 to increase platelet aggregation in response to collagen, thrombin, and ADP, 31 the underlying functional and signaling mechanisms that are involved in this process were not studied. In the present .…”

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confidence: 99%

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Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway

Hers

2007

Blood

105

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IntroductionVascular damage leads to the rapid recruitment of platelets to the site of injury. Platelets adhere to the newly exposed von Willebrand factor (VWF) and collagen in the extracellular matrix, leading to subsequent platelet activation and the secretion of dense and ␣ granule content into the extracellular media. Platelet granules contain a range of autocrine agonists that can activate or modulate the function of other platelets to form aggregates, including ADP, serotonin, and possibly Gas6 1,2 and tachykinins. 3 Another factor that is found in the ␣ granules in platelets is insulin-like growth factor-1 (IGF-1), 4,5 a growth factor involved in cell proliferation, differentiation, and migration. 6 The presence of IGF-1 at the site of vascular injury is essential in the wound-healing process, 7 and local delivery by platelets may therefore support the healing process.IGF-1 is a peptide hormone whose concentration in plasma increases in response to growth hormone, largely due to increased production by the liver. 8 The effect of IGF-1 is modulated by multiple IGF-binding proteins (IGFBPs), which bind IGF-1 and thereby serve as transporter proteins and storage pools. 6 The receptor for IGF-1 has a wide tissue expression and is closely related to the insulin receptor. The insulin receptor is involved in plasma glucose homeostasis and therefore signals mainly to metabolic responses, whereas the IGF receptor couples primarily to mitogenic responses. Both receptors are heterodimers composed of two ligand-binding ␣ subunits linked by disulphide bridges to two transmembrane ␤ subunits that possess ligand-stimulated tyrosine kinase activity. Ligand binding and subsequent activation leads to the phosphorylation of the major substrates Shc and the insulin receptor substrate (IRS) proteins IRS-1 and IRS-2. Tyrosine phosphorylation of IRS proteins on specific residues creates binding sites for Src homology (SH2)-containing proteins such as the tyrosine phosphatase SHP-2 and the regulatory p85 subunit of phosphoinositide-3 kinase (PI3K), thereby increasing their enzyme activity and/or localizing them to their substrates. Activation of PI3K leads to a rapid rise in PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 , which results in the recruitment of protein kinase B (PKB) to the plasma membrane and subsequent phosphorylation of PKB on Thr308 by PDK1 and Ser473 by second kinase, which is likely to be the mTOR/Rictor complex. 9 Subsequent activation of PKB is involved in numerous cellular responses to insulin and IGF-1. 10,11 Insulin resistance and altered blood IGF-1 levels have been implicated in the development of cardiovascular disease. 12,13 Insulin resistance is described as the reduced ability of insulin to lower glucose concentrations in the blood, and is closely associated with obesity and diabetes. 13 Increased free IGF-1 levels and decreased levels of IGFBP-1 are found in serum of obese subjects compared with lean subjects, whereas total IGF-1 levels are within the normal range. 14 Raised local levels of IGF-1 are also li...

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Section: Discussionmentioning

confidence: 99%

Section: Igf-1 Stimulates Rapid Phosphorylation Of the Igf Receptor Omentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway

Hers

2007

Blood

105

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“…[1][2][3][4] IGF-1 alone is unable to activate platelets, but in combination with activating stimuli potentiates various platelet functional responses. [5][6][7] IGF-1 is a peptide hormone that mediates its function by binding to the transmembrane IGF-1 receptor, which is highly expressed on the platelet plasma membrane 8,9 and in a wide variety of other tissues. The receptor shares a high degree of homology with the insulin receptor, with recent studies demonstrating the ability of IGF-1 to signal via IGF-1/insulin hybrid receptors in platelets.…”

mentioning

confidence: 99%

Phosphoinositide 3-Kinases p110α and p110β Have Differential Roles in Insulin-Like Growth Factor-1–Mediated Akt Phosphorylation and Platelet Priming

Blair

Moore

Williams

et al. 2014

ATVB

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Objective-Platelet hyperactivity is a contributing factor in the pathogenesis of cardiovascular disease and can be induced by elevated levels of circulating growth factors, such as insulin-like growth factor-1 (IGF-1). IGF-1 is a primer that cannot stimulate platelet activation by itself, but in combination with physiological stimuli can potentiate platelet functional responses via a phosphoinositide 3-kinase-dependent mechanism. In this study, we explored the role of the phosphoinositide 3-kinase p110α isoform in IGF-1-mediated enhancement of platelet function. Approach and Results-Using a platelet-specific p110α knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110α, did not affect proteinase-activated receptor 4 signaling to Akt/protein kinase B but significantly reduced IGF-1-mediated Akt phosphorylation. The p110β inhibitor TGX-221 abolished IGF-1-induced Akt phosphorylation in p110α-deficient platelets, demonstrating that both p110α and p110β contribute to IGF-1-mediated Akt phosphorylation. Genetic deletion of p110α had no effect on IGF-1-mediated increases in thrombus formation on collagen and enhancement of proteinase-activated receptor 4-mediated integrin activation and α-granule secretion. In contrast, pharmacological inhibition of p110α blocked IGF-1-mediated potentiation of integrin activation and α-granule secretion. Functional enhancement by IGF-1 in p110α knockout samples was lost after TGX-221 treatment, suggesting that p110β drives priming in the absence of the p110α isoform. Conclusions-Together, these results demonstrate that both p110α and p110β are involved in Akt signaling by IGF-1, but that it is the p110α isoform that is responsible for IGF-1-mediated potentiation of platelet function.

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Autologous Platelet‐Based Therapies

Arm

2006

Wiley Encyclopedia of Biomedical Engineering

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Healing and fusion in challenging bone grafting procedures is not guaranteed using the gold standard of autogenous iliac crest bone, and clinicians are increasingly interested in tissue engineering solutions using cells and signaling factors to enhance both overall success rate and time to fusion. The potential role in wound repair from application of cytokines contained in platelets was initially described more than 20 years ago. A rapid, simple preparation method to perioperatively separate and collect the platelet‐rich fraction was developed a decade later, expanding the potential range of clinical applications. Numerous additional point‐of‐care techniques have since been introduced, potentially providing a cost‐effective alternative to single recombinant proteins. As with many emerging technologies, clinicians are confronted with a frequently conflicting array of largely anecdotal claims for clinical utility. With a focus on structural bone graft repair, this chapter will present the therapeutic basis for clinical use of topically applied autogenous growth factor preparations and summarize existing experimental and application‐specific clinical outcomes reports.

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Demonstration of Type I Insulin-Like Growth Factor Receptors on Human Platelets

Cited by 19 publications

References 27 publications

Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway

Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway

Phosphoinositide 3-Kinases p110α and p110β Have Differential Roles in Insulin-Like Growth Factor-1–Mediated Akt Phosphorylation and Platelet Priming

Autologous Platelet‐Based Therapies

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