Insulin-like growth factor-1 regulates platelet activation through PI3-Kα isoform

Kim, Soochong; Garcia, Analia; Jackson, Shaun P.; Kunapuli, Satya P.

doi:10.1182/blood-2007-03-080804

Cited by 58 publications

(58 citation statements)

References 50 publications

(89 reference statements)

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“…We and others previously found that IGF-1-stimulated Akt phosphorylation in human platelets was ablated on pretreatment with the p110α inhibitor PIK-75. 6,7 Here, we find that IGF-1 also stimulates a dose-dependent increase in Akt phosphorylation in mouse platelets ( Figure 2C), reaching maximal phosphorylation at 5 minutes ( Figure 2D). Loss of p110α significantly reduced, but did not block, IGF-1-mediated Akt phosphorylation ( Figure 2C and 2D).…”

Section: Deletion Of P110α Results In a Reduction In Igf-1-mediated Bmentioning

confidence: 59%

“…[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%

“…21 Recent studies using isoform-selective inhibitors implied that p110α may contribute to thrombus formation 19,22 and IGF-1-mediated potentiation of platelet function. 6,7 Platelets play a critical role in hemostasis and have been implicated in the pathogenesis of cardiovascular disease. 23 Interestingly, platelet primers such as IGF-1 are able to modulate platelet function, and altered levels of such primers may contribute to the development of cardiovascular disease.…”

mentioning

confidence: 99%

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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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Section: Deletion Of P110α Results In a Reduction In Igf-1-mediated Bmentioning

confidence: 59%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…26,47 Interestingly, an important role for the PI3K/AKT pathway has been shown to stimulate FOXO3A and FOXG1 phosphorylation via epinephrine or IGF1, respectively. 9,49 The PI3K/AKT pathway is also known to be important as an amplification signaling pathway for initial platelet activation via epinephrine 50 and ADP. 51 Further studies are needed to define whether FOXG1 is also essential in this pathway to obtain full platelet activation.…”

Section: Discussionmentioning

confidence: 99%

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

Goubau

Devriendt

et al. 2013

Eur J Hum Genet

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The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C4G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells.

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“…Thrombin mediated platelet aggregation via PAR-1 is potentiated by IGF-1 and this is reversed by PI3Kα inhibitors. The contribution of PI3K p110α for activation of AKT demonstrates that IGF-1 potentiates platelet aggregation by complementing the Gi (linked to PI3Kβ) but not the Gq-signaling pathways [11][12][13]. Although IGF-1 is not considered a major player in platelet function, data from several phase I and phase II studies of IGF1R inhibitors have shown their presence is associated with some evidence of bleeding (GI) and thrombocytopenia [14].…”

Section: Insulin (Ins) Familymentioning

confidence: 99%

Receptor Tyrosine Kinases in Human Platelets: A Review of Expression, Function and Inhibition in Relation to the Risk of Bleeding or Thrombocytopenia from Phase I through Phase III Trials

Sater¹,

G²,

et al. 2017

JCPCR

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Tyrosine kinases (TKs) are divided into two main categories: receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases (NRTK). RTKs include approximately 21 families. Examples of RTKs are epidermal growth factor receptor (EGFR), plateletderived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Tyrosine Kinase Inhibitors (TKIs) are used to treat both hematologic and solid malignancies. They have variable side effects, one of which is a platelet type bleeding diathesis.

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Insulin-like growth factor-1 regulates platelet activation through PI3-Kα isoform

Cited by 58 publications

References 50 publications

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

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

Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12

Receptor Tyrosine Kinases in Human Platelets: A Review of Expression, Function and Inhibition in Relation to the Risk of Bleeding or Thrombocytopenia from Phase I through Phase III Trials

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