Insulin-like Growth Factor-1 Regulates Endogenous RUNX2 Activity in Endothelial Cells through a Phosphatidylinositol 3-Kinase/ERK-dependent and Akt-independent Signaling Pathway

Qiao, Meng; Shapiro, Paul; Kumar, Rakesh; Passaniti, Antonino

doi:10.1074/jbc.m404480200

Cited by 133 publications

(112 citation statements)

References 62 publications

Supporting

Mentioning

102

Contrasting

Order By: Relevance

“…It is worth noting that siRNA-mediated knockdown of Akt1 did not lead to AMPK or ACC hyperphosphorylation, in contrast to the hyperphosphorylation effect seen with the PI3K inhibitor wortmannin. We speculate that this difference between the effects of wortmannin versus Akt1 siRNA may reflect Akt-independent signaling downstream of PI3K, perhaps involving the MAPK pathway, as has been proposed in a number of recent reports (52,53). Further studies will be necessary to determine whether AMPK can directly activate eNOS in a pathway that does not involve Akt.…”

Section: Discussionmentioning

confidence: 94%

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

Levine

Michel

2007

Journal of Biological Chemistry

192

View full text Add to dashboard Cite

The endothelial isoform of nitric-oxide synthase (eNOS), a key determinant of vascular homeostasis, is a calcium/calmodulindependent phosphoprotein regulated by diverse cell surface receptors. Vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) stimulate eNOS activity through Akt/phosphoinositide 3-kinase and calcium-dependent pathways. AMP-activated protein kinase (AMPK) also activates eNOS in endothelial cells; however, the molecular mechanisms linking agonist-mediated AMPK regulation with eNOS activation remain incompletely understood. We studied the role of AMPK in VEGF-and S1P-mediated eNOS activation and found that both agonists led to a striking increase in AMPK phosphorylation in pathways involving the calcium/calmodulin-dependent protein kinase kinase ␤. Treatment with tyrosine kinase inhibitors or the phosphoinositide 3-kinase inhibitor wortmannin demonstrated differential effects of VEGF versus S1P. Small interfering RNA (siRNA)-mediated knockdown of AMPK␣1 or Akt1 impaired the stimulatory effects of both VEGF and S1P on eNOS activation. AMPK␣1 knockdown impaired agonist-mediated Akt phosphorylation, whereas Akt1 knockdown did not affect AMPK activation, thus suggesting that AMPK lies upstream of Akt in the pathway leading from receptor activation to eNOS stimulation. Importantly, we found that siRNA-mediated knockdown of AMPK␣1 abrogates agonist-mediated activation of the small GTPase Rac1. Conversely, siRNA-mediated knockdown of Rac1 decreased the agonist-mediated phosphorylation of AMPK substrates without affecting that of AMPK, implicating Rac1 as a molecular link between AMPK and Akt in agonist-mediated eNOS activation. Finally, siRNA-mediated knockdown of caveolin-1 significantly enhanced AMPK phosphorylation, suggesting that AMPK is negatively regulated by caveolin-1. Taken together, these results suggest that VEGF and S1P differentially regulate AMPK and establish a central role for an agonist-modulated AMPK 3 Rac1 3 Akt axis in the control of eNOS in endothelial cells.

show abstract

Section: Discussionmentioning

confidence: 94%

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

Levine

Michel

2007

Journal of Biological Chemistry

192

View full text Add to dashboard Cite

show abstract

“…In human bronchial epithelial cells, cigarette smoke-induced epidermal growth factor receptor-mediated activation of FRA-1 expression is carried out by the PI3K-(PAK-1)-(Raf)-MEK-ERK signaling cascade, without the participation of Akt (Li et al, 2005;Zhang et al, 2006). In addition, Qiao et al (2004) reported that IGF-1 stimulates the activity of the transcription factor RUNX2, through a PI3K-dependent but Akt-independent signaling pathway. Both Fra-1 and Runx2 are known downstream targets of the Wnt or cat/TCF signaling pathway (Mann et al, 1999;Dong et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

View full text Add to dashboard Cite

Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulinlike growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Aktindependent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in b-catenin (b-cat) in the nucleus and an increased association between b-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/ activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and b-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated b-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear b-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

show abstract

“…Similarly, deletion of Igf1r in the osteoblast lineage impaired bone formation (25,26). Mechanistically, Igf signaling has been proposed to stimulate Runx2 activity downstream of either Akt or Erk (27,28). We have shown that Igf and Ihh signaling control cartilage development largely independently, but it is not known whether the two signals intersect during osteoblast differentiation (29).…”

mentioning

confidence: 94%

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Shi¹,

Chen²,

Karner³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program.

show abstract

Insulin-like Growth Factor-1 Regulates Endogenous RUNX2 Activity in Endothelial Cells through a Phosphatidylinositol 3-Kinase/ERK-dependent and Akt-independent Signaling Pathway

Cited by 133 publications

References 62 publications

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation

Contact Info

Product

Resources

About