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PIKE GTPase are phosphoinositide-3-kinase enhancers, suppressing programmed cell death.

Chan CB, Ye K - J. Cell. Mol. Med. (2007 Jan-Feb)

Bottom Line: PIKE-A does not interplay with PI3K.Instead, it interacts with the downstream effector Akt and promotes its activity.Because both PI3K and Akt are important effectors in the growth factor-mediated signaling which triggers cellular growth and acts against apoptosis, PIKEs therefore serve as the molecular switch that their activation are crucial for growth factors to exert their physiological functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

ABSTRACT
Phosphoinositide-3-kinase enhancers (PIKE) are GTP-binding proteins that posses anti-apoptotic functions. The PIKE family includes three members, PIKE-L, PIKE-S and PIKE-A, which are originated from a single gene (CENTG1) through alternative splicing or differential transcription initiation. Both PIKE-S and PIKE-L bind to phosphoinositide-3-kinase (PI3K) and enhance its activity. PIKE-A does not interplay with PI3K. Instead, it interacts with the downstream effector Akt and promotes its activity. These actions are mediated by their GTPase activity. Because both PI3K and Akt are important effectors in the growth factor-mediated signaling which triggers cellular growth and acts against apoptosis, PIKEs therefore serve as the molecular switch that their activation are crucial for growth factors to exert their physiological functions. In this review, the current understanding of different PIKE isoforms in growth factors-induced anti-apoptotic function will be discussed. Moreover, the role of PIKE in the survival and invasion activity of cancer cells will also be introduced.

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A summary of PIKE signaling pathways.
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fig02: A summary of PIKE signaling pathways.

Mentions: Like Ras GTPase, PIKE-S showed a specific binding to GTP and hydrolyzed bound GTP into GDP. This GTP-loading was further increased in the presence of NGF [23]. These results suggest that PIKE-S is a functional GTP-binding protein in which its activity could be regulated by its intrinsic GTPase cycle: in the inactive state, GDP was bound to the GTP-binding domain whereas upon upstream signal stimulation, e.g. NGF stimulation, the GDP is replaced with GTP leading to the conformational change of the effector-binding region so that the region interacts with the downstream effectors. After activation, the GTP is hydrolyzed into GDP by its GTPase activity and thus returns to the resting state when the bound effector is released [31]. Further characterizations of PIKE-S indicated that it also bound to both p85 and p110 sub-units of PI3K in which the interactions consequently enhanced its activity.This augmentation of PI3K activity was GTPase dependant as interaction of a PIKE-S/K413AS414N) mutant, a mutation that abolished the GTP binding activity of PIKE-S, failed to activate PI3K. Moreover, the PIKE-S-stimulated PI3K activity was further enhanced by NGF stimulation. The temporal profile of PIKE-S activation, as shown by GTP-loading assay, correlated well with the enhanced PI3K activity after NGF treatment in which maximal activities of both proteins occurred 30 min after NGF stimulation and returned to basal level after 4 hrs [23]. Because PIKE-S is a nuclear specific protein, these observations, together with the fact that PIKE-S is an NGF-activated GTPase, reveal that PIKE-S is a regulator of PI3K activity in the nucleus (Fig. 2).


PIKE GTPase are phosphoinositide-3-kinase enhancers, suppressing programmed cell death.

Chan CB, Ye K - J. Cell. Mol. Med. (2007 Jan-Feb)

A summary of PIKE signaling pathways.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401219&req=5

fig02: A summary of PIKE signaling pathways.
Mentions: Like Ras GTPase, PIKE-S showed a specific binding to GTP and hydrolyzed bound GTP into GDP. This GTP-loading was further increased in the presence of NGF [23]. These results suggest that PIKE-S is a functional GTP-binding protein in which its activity could be regulated by its intrinsic GTPase cycle: in the inactive state, GDP was bound to the GTP-binding domain whereas upon upstream signal stimulation, e.g. NGF stimulation, the GDP is replaced with GTP leading to the conformational change of the effector-binding region so that the region interacts with the downstream effectors. After activation, the GTP is hydrolyzed into GDP by its GTPase activity and thus returns to the resting state when the bound effector is released [31]. Further characterizations of PIKE-S indicated that it also bound to both p85 and p110 sub-units of PI3K in which the interactions consequently enhanced its activity.This augmentation of PI3K activity was GTPase dependant as interaction of a PIKE-S/K413AS414N) mutant, a mutation that abolished the GTP binding activity of PIKE-S, failed to activate PI3K. Moreover, the PIKE-S-stimulated PI3K activity was further enhanced by NGF stimulation. The temporal profile of PIKE-S activation, as shown by GTP-loading assay, correlated well with the enhanced PI3K activity after NGF treatment in which maximal activities of both proteins occurred 30 min after NGF stimulation and returned to basal level after 4 hrs [23]. Because PIKE-S is a nuclear specific protein, these observations, together with the fact that PIKE-S is an NGF-activated GTPase, reveal that PIKE-S is a regulator of PI3K activity in the nucleus (Fig. 2).

Bottom Line: PIKE-A does not interplay with PI3K.Instead, it interacts with the downstream effector Akt and promotes its activity.Because both PI3K and Akt are important effectors in the growth factor-mediated signaling which triggers cellular growth and acts against apoptosis, PIKEs therefore serve as the molecular switch that their activation are crucial for growth factors to exert their physiological functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

ABSTRACT
Phosphoinositide-3-kinase enhancers (PIKE) are GTP-binding proteins that posses anti-apoptotic functions. The PIKE family includes three members, PIKE-L, PIKE-S and PIKE-A, which are originated from a single gene (CENTG1) through alternative splicing or differential transcription initiation. Both PIKE-S and PIKE-L bind to phosphoinositide-3-kinase (PI3K) and enhance its activity. PIKE-A does not interplay with PI3K. Instead, it interacts with the downstream effector Akt and promotes its activity. These actions are mediated by their GTPase activity. Because both PI3K and Akt are important effectors in the growth factor-mediated signaling which triggers cellular growth and acts against apoptosis, PIKEs therefore serve as the molecular switch that their activation are crucial for growth factors to exert their physiological functions. In this review, the current understanding of different PIKE isoforms in growth factors-induced anti-apoptotic function will be discussed. Moreover, the role of PIKE in the survival and invasion activity of cancer cells will also be introduced.

Show MeSH
Related in: MedlinePlus