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The Role of the PI3K Pathway in the Regeneration of the Damaged Brain by Neural Stem Cells after Cerebral Infarction.

Koh SH, Lo EH - J Clin Neurol (2015)

Bottom Line: Neurologic deficits resulting from stroke remain largely intractable, which has prompted thousands of studies aimed at developing methods for treating these neurologic sequelae.The phosphatidylinositol-3-kinase (PI3K) pathway is known to play important roles in cell survival, and many studies have focused on use of the PI3K pathway to treat brain injury after stroke.Furthermore, since the PI3K pathway may also play key roles in the physiology of neural stem cells (NSCs), eliciting the appropriate activation of the PI3K pathway in NSCs may help to improve the sequelae of cerebral infarction.

View Article: PubMed Central - PubMed

Affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ksh213@hanyang.ac.kr.

ABSTRACT
Neurologic deficits resulting from stroke remain largely intractable, which has prompted thousands of studies aimed at developing methods for treating these neurologic sequelae. Endogenous neurogenesis is also known to occur after brain damage, including that due to cerebral infarction. Focusing on this process may provide a solution for treating neurologic deficits caused by cerebral infarction. The phosphatidylinositol-3-kinase (PI3K) pathway is known to play important roles in cell survival, and many studies have focused on use of the PI3K pathway to treat brain injury after stroke. Furthermore, since the PI3K pathway may also play key roles in the physiology of neural stem cells (NSCs), eliciting the appropriate activation of the PI3K pathway in NSCs may help to improve the sequelae of cerebral infarction. This review describes the PI3K pathway, its roles in the brain and NSCs after cerebral infarction, and the therapeutic possibility of activating the pathway to improve neurologic deficits after cerebral infarction.

No MeSH data available.


Related in: MedlinePlus

Role of the phosphatidylinositol-3-kinase (PI3K) pathway in cells. Akt: protein kinase B, BAD: Bcl-2-associated death promoter, FOXO1: forkhead box protein O1, GSK3β: glycogen synthase kinase 3β, MDM2: mouse double minute 2 homolog, mTOR: mammalian target of rapamycin, NF-kB: nuclear factor kappa-light-chain enhancer of activated B cells, PKC: protein kinase C, Ptdlns: phosphatidylinositol, PTEN: phosphatase and tensin homolog, RAC1: Ras-related C3 botulinum toxin substrate 1, SGK: serine/threonine-protein kinase, S6K: ribosomal protein S6 kinase.
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Figure 1: Role of the phosphatidylinositol-3-kinase (PI3K) pathway in cells. Akt: protein kinase B, BAD: Bcl-2-associated death promoter, FOXO1: forkhead box protein O1, GSK3β: glycogen synthase kinase 3β, MDM2: mouse double minute 2 homolog, mTOR: mammalian target of rapamycin, NF-kB: nuclear factor kappa-light-chain enhancer of activated B cells, PKC: protein kinase C, Ptdlns: phosphatidylinositol, PTEN: phosphatase and tensin homolog, RAC1: Ras-related C3 botulinum toxin substrate 1, SGK: serine/threonine-protein kinase, S6K: ribosomal protein S6 kinase.

Mentions: It is well known that the PI3Ks are involved in various cellular functions, such as cell proliferation, growth, differentiation, motility, survival, and intracellular trafficking. The PI3K pathway is necessary for the survival of both neurons and NSCs.1011 PI3K is not a single enzyme, but rather a family of many different subtypes. The PI3K family is divided into three different classes (Class I, Class II, and Class III) based on the primary structure, regulation, and in vitro lipid substrate specificity.12 Among these, the Class I PI3Ks are the best understood and can be divided into two groups: Class IA (p110α, p110β, and p110δ) and Class IB (p110γ).13 The PI3K pathway is known to interact with the insulin receptor substrate (IRS) and is closely linked with the tumor suppressor phosphatase and tensin homolog (PTEN), which inhibits PI3Ks. When the IRS is activated by insulin, it activates PI3Ks and then regulates glucose uptake through diverse phosphorylation events. In detail, activated PI3Ks phosphorylate the 3-position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns) to produce phosphoinositide Ptdlns(3,4,5)P3 from Ptdlns(4,5)P2.1415 Ptdlns(3,4,5)P3 activates many different downstream effectors, the most well known of which is Akt (protein kinase B).16 Akt phosphorylated by PI3Ks (pAkt) affects many important downstream signals, including mouse double minute 2 homolog (MDM2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), endothelial nitric oxide synthase (eNOS), mammalian target of rapamycin (mTOR), and S6 kinase, and inhibits Forkhead box O (FOXO)s, BAD, and glycogen synthase kinase (GSK)-3β.1617 These effects contribute to growth, translation, and cell-cycle regulation, glucose metabolism, DNA repair, and inhibition of apoptosis (Fig. 1).1617


The Role of the PI3K Pathway in the Regeneration of the Damaged Brain by Neural Stem Cells after Cerebral Infarction.

Koh SH, Lo EH - J Clin Neurol (2015)

Role of the phosphatidylinositol-3-kinase (PI3K) pathway in cells. Akt: protein kinase B, BAD: Bcl-2-associated death promoter, FOXO1: forkhead box protein O1, GSK3β: glycogen synthase kinase 3β, MDM2: mouse double minute 2 homolog, mTOR: mammalian target of rapamycin, NF-kB: nuclear factor kappa-light-chain enhancer of activated B cells, PKC: protein kinase C, Ptdlns: phosphatidylinositol, PTEN: phosphatase and tensin homolog, RAC1: Ras-related C3 botulinum toxin substrate 1, SGK: serine/threonine-protein kinase, S6K: ribosomal protein S6 kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596106&req=5

Figure 1: Role of the phosphatidylinositol-3-kinase (PI3K) pathway in cells. Akt: protein kinase B, BAD: Bcl-2-associated death promoter, FOXO1: forkhead box protein O1, GSK3β: glycogen synthase kinase 3β, MDM2: mouse double minute 2 homolog, mTOR: mammalian target of rapamycin, NF-kB: nuclear factor kappa-light-chain enhancer of activated B cells, PKC: protein kinase C, Ptdlns: phosphatidylinositol, PTEN: phosphatase and tensin homolog, RAC1: Ras-related C3 botulinum toxin substrate 1, SGK: serine/threonine-protein kinase, S6K: ribosomal protein S6 kinase.
Mentions: It is well known that the PI3Ks are involved in various cellular functions, such as cell proliferation, growth, differentiation, motility, survival, and intracellular trafficking. The PI3K pathway is necessary for the survival of both neurons and NSCs.1011 PI3K is not a single enzyme, but rather a family of many different subtypes. The PI3K family is divided into three different classes (Class I, Class II, and Class III) based on the primary structure, regulation, and in vitro lipid substrate specificity.12 Among these, the Class I PI3Ks are the best understood and can be divided into two groups: Class IA (p110α, p110β, and p110δ) and Class IB (p110γ).13 The PI3K pathway is known to interact with the insulin receptor substrate (IRS) and is closely linked with the tumor suppressor phosphatase and tensin homolog (PTEN), which inhibits PI3Ks. When the IRS is activated by insulin, it activates PI3Ks and then regulates glucose uptake through diverse phosphorylation events. In detail, activated PI3Ks phosphorylate the 3-position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns) to produce phosphoinositide Ptdlns(3,4,5)P3 from Ptdlns(4,5)P2.1415 Ptdlns(3,4,5)P3 activates many different downstream effectors, the most well known of which is Akt (protein kinase B).16 Akt phosphorylated by PI3Ks (pAkt) affects many important downstream signals, including mouse double minute 2 homolog (MDM2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), endothelial nitric oxide synthase (eNOS), mammalian target of rapamycin (mTOR), and S6 kinase, and inhibits Forkhead box O (FOXO)s, BAD, and glycogen synthase kinase (GSK)-3β.1617 These effects contribute to growth, translation, and cell-cycle regulation, glucose metabolism, DNA repair, and inhibition of apoptosis (Fig. 1).1617

Bottom Line: Neurologic deficits resulting from stroke remain largely intractable, which has prompted thousands of studies aimed at developing methods for treating these neurologic sequelae.The phosphatidylinositol-3-kinase (PI3K) pathway is known to play important roles in cell survival, and many studies have focused on use of the PI3K pathway to treat brain injury after stroke.Furthermore, since the PI3K pathway may also play key roles in the physiology of neural stem cells (NSCs), eliciting the appropriate activation of the PI3K pathway in NSCs may help to improve the sequelae of cerebral infarction.

View Article: PubMed Central - PubMed

Affiliation: Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ksh213@hanyang.ac.kr.

ABSTRACT
Neurologic deficits resulting from stroke remain largely intractable, which has prompted thousands of studies aimed at developing methods for treating these neurologic sequelae. Endogenous neurogenesis is also known to occur after brain damage, including that due to cerebral infarction. Focusing on this process may provide a solution for treating neurologic deficits caused by cerebral infarction. The phosphatidylinositol-3-kinase (PI3K) pathway is known to play important roles in cell survival, and many studies have focused on use of the PI3K pathway to treat brain injury after stroke. Furthermore, since the PI3K pathway may also play key roles in the physiology of neural stem cells (NSCs), eliciting the appropriate activation of the PI3K pathway in NSCs may help to improve the sequelae of cerebral infarction. This review describes the PI3K pathway, its roles in the brain and NSCs after cerebral infarction, and the therapeutic possibility of activating the pathway to improve neurologic deficits after cerebral infarction.

No MeSH data available.


Related in: MedlinePlus