Limits...
A specific role for phosphoinositide 3-kinase and AKT in osteoblasts?

McGonnell IM, Grigoriadis AE, Lam EW, Price JS, Sunters A - Front Endocrinol (Lausanne) (2012)

Bottom Line: With regard to bone, and particularly in osteoblasts, there is an increasing amount of evidence that the many signaling molecules exert some of their bone-specific effects in part via selectively activating some of the generic effects of the PI3K/AKT pathway in osteoblasts.There is also evidence that perturbations in the PI3K/AKT pathway may well be responsible for certain bone pathologies.In this review, we discuss some of these findings and suggest that the PI3K/AKT pathway is a central nexus in the extensive network of extracellular signaling pathways that control the osteoblast.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, London, UK.

ABSTRACT
The phosphoinositide 3-kinase and AKT (protein kinase B) signaling pathway (PI3K/AKT) plays a central role in the control of cell survival, growth, and proliferation throughout the body. With regard to bone, and particularly in osteoblasts, there is an increasing amount of evidence that the many signaling molecules exert some of their bone-specific effects in part via selectively activating some of the generic effects of the PI3K/AKT pathway in osteoblasts. There is further data demonstrating that PI3K/AKT has the capacity to specifically cross-talk with other signaling pathways and transcriptional networks controlling bone cells' development in order to fine-tune the osteoblast phenotype. There is also evidence that perturbations in the PI3K/AKT pathway may well be responsible for certain bone pathologies. In this review, we discuss some of these findings and suggest that the PI3K/AKT pathway is a central nexus in the extensive network of extracellular signaling pathways that control the osteoblast.

No MeSH data available.


Related in: MedlinePlus

A model depicting PI3K signaling. Binding of the receptor tyrosine kinase ligand activates receptor auto-phosphorylation, leading to recruitment of substrate proteins such as IRS-1. This leads to recruitment of the regulatory (p85) and catalytic (p110) subunits of class 1a PI3K. PI3K phosphorylation of PIP2 to PIP3 allows PIP3 to act as a secondary messenger within the inner surface of the cell membrane. AKT and PDK1 bind to PIP3, and PDK1 and mTOR/Rictor activate AKT via phosphorylation. Active AKT is then able to promote cell survival, growth, and proliferation by phosphorylation of key substrates. Also shown is the alternative Ras pathway which can also be stimulated by receptor tyrosine kinases to activate MAPKs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3400941&req=5

Figure 1: A model depicting PI3K signaling. Binding of the receptor tyrosine kinase ligand activates receptor auto-phosphorylation, leading to recruitment of substrate proteins such as IRS-1. This leads to recruitment of the regulatory (p85) and catalytic (p110) subunits of class 1a PI3K. PI3K phosphorylation of PIP2 to PIP3 allows PIP3 to act as a secondary messenger within the inner surface of the cell membrane. AKT and PDK1 bind to PIP3, and PDK1 and mTOR/Rictor activate AKT via phosphorylation. Active AKT is then able to promote cell survival, growth, and proliferation by phosphorylation of key substrates. Also shown is the alternative Ras pathway which can also be stimulated by receptor tyrosine kinases to activate MAPKs.

Mentions: The PI3K pathway is activated through the receptor tyrosine kinase (RTK) class of receptors which include fibroblast growth factor receptors (FGFRs), insulin-like growth factor receptors (IGFRs), and insulin receptor (Figure 1). Engagement of the ligand with the RTK causes autophosphorylation of tyrosine residues in the cytoplasmic domain. These phosphorylated tyrosine residues then recruit docking proteins, most notably IRS1, which in turn recruits the p85 subunit of PI3K. PI3K itself consists of a regulatory p85 subunit and a catalytic p110 subunit. Recruitment of the PI3K complex to the inner surface of the plasma membrane juxtaposes it with its substrate phosphatidylinositol-4,5 diphosphate (PIP2) located in the inner lamina of the cell membrane. PIP2 is then phosphorylated by the p110 subunit to form phosphatidylinositol-3,4,5 trisphosphate (PIP3). The conversion of PIP3 to PIP2, and the subsequent inactivation of PI3K downstream signaling, is facilitated by the tumor suppressor and phosphatase; phosphatase and tensin homolog deleted on chromosome ten (PTEN) (Cantley and Neel, 1999).


A specific role for phosphoinositide 3-kinase and AKT in osteoblasts?

McGonnell IM, Grigoriadis AE, Lam EW, Price JS, Sunters A - Front Endocrinol (Lausanne) (2012)

A model depicting PI3K signaling. Binding of the receptor tyrosine kinase ligand activates receptor auto-phosphorylation, leading to recruitment of substrate proteins such as IRS-1. This leads to recruitment of the regulatory (p85) and catalytic (p110) subunits of class 1a PI3K. PI3K phosphorylation of PIP2 to PIP3 allows PIP3 to act as a secondary messenger within the inner surface of the cell membrane. AKT and PDK1 bind to PIP3, and PDK1 and mTOR/Rictor activate AKT via phosphorylation. Active AKT is then able to promote cell survival, growth, and proliferation by phosphorylation of key substrates. Also shown is the alternative Ras pathway which can also be stimulated by receptor tyrosine kinases to activate MAPKs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3400941&req=5

Figure 1: A model depicting PI3K signaling. Binding of the receptor tyrosine kinase ligand activates receptor auto-phosphorylation, leading to recruitment of substrate proteins such as IRS-1. This leads to recruitment of the regulatory (p85) and catalytic (p110) subunits of class 1a PI3K. PI3K phosphorylation of PIP2 to PIP3 allows PIP3 to act as a secondary messenger within the inner surface of the cell membrane. AKT and PDK1 bind to PIP3, and PDK1 and mTOR/Rictor activate AKT via phosphorylation. Active AKT is then able to promote cell survival, growth, and proliferation by phosphorylation of key substrates. Also shown is the alternative Ras pathway which can also be stimulated by receptor tyrosine kinases to activate MAPKs.
Mentions: The PI3K pathway is activated through the receptor tyrosine kinase (RTK) class of receptors which include fibroblast growth factor receptors (FGFRs), insulin-like growth factor receptors (IGFRs), and insulin receptor (Figure 1). Engagement of the ligand with the RTK causes autophosphorylation of tyrosine residues in the cytoplasmic domain. These phosphorylated tyrosine residues then recruit docking proteins, most notably IRS1, which in turn recruits the p85 subunit of PI3K. PI3K itself consists of a regulatory p85 subunit and a catalytic p110 subunit. Recruitment of the PI3K complex to the inner surface of the plasma membrane juxtaposes it with its substrate phosphatidylinositol-4,5 diphosphate (PIP2) located in the inner lamina of the cell membrane. PIP2 is then phosphorylated by the p110 subunit to form phosphatidylinositol-3,4,5 trisphosphate (PIP3). The conversion of PIP3 to PIP2, and the subsequent inactivation of PI3K downstream signaling, is facilitated by the tumor suppressor and phosphatase; phosphatase and tensin homolog deleted on chromosome ten (PTEN) (Cantley and Neel, 1999).

Bottom Line: With regard to bone, and particularly in osteoblasts, there is an increasing amount of evidence that the many signaling molecules exert some of their bone-specific effects in part via selectively activating some of the generic effects of the PI3K/AKT pathway in osteoblasts.There is also evidence that perturbations in the PI3K/AKT pathway may well be responsible for certain bone pathologies.In this review, we discuss some of these findings and suggest that the PI3K/AKT pathway is a central nexus in the extensive network of extracellular signaling pathways that control the osteoblast.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, London, UK.

ABSTRACT
The phosphoinositide 3-kinase and AKT (protein kinase B) signaling pathway (PI3K/AKT) plays a central role in the control of cell survival, growth, and proliferation throughout the body. With regard to bone, and particularly in osteoblasts, there is an increasing amount of evidence that the many signaling molecules exert some of their bone-specific effects in part via selectively activating some of the generic effects of the PI3K/AKT pathway in osteoblasts. There is further data demonstrating that PI3K/AKT has the capacity to specifically cross-talk with other signaling pathways and transcriptional networks controlling bone cells' development in order to fine-tune the osteoblast phenotype. There is also evidence that perturbations in the PI3K/AKT pathway may well be responsible for certain bone pathologies. In this review, we discuss some of these findings and suggest that the PI3K/AKT pathway is a central nexus in the extensive network of extracellular signaling pathways that control the osteoblast.

No MeSH data available.


Related in: MedlinePlus