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Regulation of autophagy by kinases.

Sridharan S, Jain K, Basu A - Cancers (Basel) (2011)

Bottom Line: Protein kinases are integral to the autophagy process.Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR.Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA. alakananda.basu@unthsc.edu.

ABSTRACT
Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

No MeSH data available.


Related in: MedlinePlus

The regulation of autophagy by several cellular kinases. PI3K: phosphoinositide 3-kinases; PDK1: phosphoinositide-dependent kinase-1; mTOR: mammalian target of rapamycin; TSC: tuberous sclerosis complex; AMPK: AMP-dependent protein kinase; ERK: extracellular signal-regulated kinase; PKC: protein kinase C.
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f1-cancers-03-02630: The regulation of autophagy by several cellular kinases. PI3K: phosphoinositide 3-kinases; PDK1: phosphoinositide-dependent kinase-1; mTOR: mammalian target of rapamycin; TSC: tuberous sclerosis complex; AMPK: AMP-dependent protein kinase; ERK: extracellular signal-regulated kinase; PKC: protein kinase C.

Mentions: Posttranslational modifications of a protein often determine its function. It is now evident that autophagy can be regulated by kinases at multiple steps such as autophagosome inception, vesicle maturation, termination and autophagy-related gene expression as depicted in Figure 1. This suggests that the process can be modulated at multiple steps for therapy. While the PI3K/mTOR pathway primarily inhibits autophagy, the role of the MAPK pathway and PKCs in autophagy may depend on the cellular context and inducers used. Also, there is extensive cross-talk among these pathways. For example, while both the PI3K and MAPK pathways are activated by receptor tyrosine kinases, the two pathways may either be antagonistic to each other or converge at the level of mTOR signaling. These pathways are activated in several cancers and play important roles in tumorigenesis and cancer progression. Differential regulation of autophagy by these two pathways could provide a tighter regulation to maintain it at levels sufficient to promote cell survival and prevent excessive self-eating and cell death. While one pathway initiates autophagy, the other pathway might be instrumental in its completion or can provide inhibitory signals at a later time to prevent excessive catabolism. Hence, the ultimate outcome will depend upon factors such as which autophagy regulatory pathways prevail, the extent of autophagy occurring and the presence of feedback control mechanisms. Our current knowledge and future work in the area of autophagy regulation should aid in designing better therapeutic approaches for cancer.


Regulation of autophagy by kinases.

Sridharan S, Jain K, Basu A - Cancers (Basel) (2011)

The regulation of autophagy by several cellular kinases. PI3K: phosphoinositide 3-kinases; PDK1: phosphoinositide-dependent kinase-1; mTOR: mammalian target of rapamycin; TSC: tuberous sclerosis complex; AMPK: AMP-dependent protein kinase; ERK: extracellular signal-regulated kinase; PKC: protein kinase C.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757434&req=5

f1-cancers-03-02630: The regulation of autophagy by several cellular kinases. PI3K: phosphoinositide 3-kinases; PDK1: phosphoinositide-dependent kinase-1; mTOR: mammalian target of rapamycin; TSC: tuberous sclerosis complex; AMPK: AMP-dependent protein kinase; ERK: extracellular signal-regulated kinase; PKC: protein kinase C.
Mentions: Posttranslational modifications of a protein often determine its function. It is now evident that autophagy can be regulated by kinases at multiple steps such as autophagosome inception, vesicle maturation, termination and autophagy-related gene expression as depicted in Figure 1. This suggests that the process can be modulated at multiple steps for therapy. While the PI3K/mTOR pathway primarily inhibits autophagy, the role of the MAPK pathway and PKCs in autophagy may depend on the cellular context and inducers used. Also, there is extensive cross-talk among these pathways. For example, while both the PI3K and MAPK pathways are activated by receptor tyrosine kinases, the two pathways may either be antagonistic to each other or converge at the level of mTOR signaling. These pathways are activated in several cancers and play important roles in tumorigenesis and cancer progression. Differential regulation of autophagy by these two pathways could provide a tighter regulation to maintain it at levels sufficient to promote cell survival and prevent excessive self-eating and cell death. While one pathway initiates autophagy, the other pathway might be instrumental in its completion or can provide inhibitory signals at a later time to prevent excessive catabolism. Hence, the ultimate outcome will depend upon factors such as which autophagy regulatory pathways prevail, the extent of autophagy occurring and the presence of feedback control mechanisms. Our current knowledge and future work in the area of autophagy regulation should aid in designing better therapeutic approaches for cancer.

Bottom Line: Protein kinases are integral to the autophagy process.Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR.Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA. alakananda.basu@unthsc.edu.

ABSTRACT
Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

No MeSH data available.


Related in: MedlinePlus