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Therapeutic Implications of Targeting AKT Signaling in Melanoma.

Madhunapantula SV, Robertson GP - Enzyme Res (2011)

Bottom Line: Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease.However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use.Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

ABSTRACT
Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of PI3 kinase enzymes.  PI3 kinases are a group of enzymes involved in regulating cell growth, proliferation, differentiation, motility, and survival.  Based on structure and substrate specificity PI3 kinases have been divided into Class I (EC number: 2.7.1.153), Class II (EC number: 2.7.1.154), and Class III (2.7.1.137) enzymes.  Class I and II PI3Ks are composed of regulatory and catalytic subunits, whereas Class III contains only catalytic subunit.  Depending on the type of subunits, heteromeric Class I PI3Ks are further subdivided into Class IA and Class IB.  Whereas Class IA PI3K consists of p85 regulatory subunit and p110 catalytic subunit, the Class IB PI3K is made up of p101 regulatory subunit and p110γ catalytic subunit. Class IA PI3K is the most common PI3Ks implicated in the development of cancers.
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fig3: Schematic representation of PI3 kinase enzymes. PI3 kinases are a group of enzymes involved in regulating cell growth, proliferation, differentiation, motility, and survival. Based on structure and substrate specificity PI3 kinases have been divided into Class I (EC number: 2.7.1.153), Class II (EC number: 2.7.1.154), and Class III (2.7.1.137) enzymes. Class I and II PI3Ks are composed of regulatory and catalytic subunits, whereas Class III contains only catalytic subunit. Depending on the type of subunits, heteromeric Class I PI3Ks are further subdivided into Class IA and Class IB. Whereas Class IA PI3K consists of p85 regulatory subunit and p110 catalytic subunit, the Class IB PI3K is made up of p101 regulatory subunit and p110γ catalytic subunit. Class IA PI3K is the most common PI3Ks implicated in the development of cancers.

Mentions: Phosphatidyl inositol 3 kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 3′ hydroxyl group of phosphatidylinositols (Pis) and phosphoinositides [66, 67]. Activation of PI3K affects cell growth, proliferation and survival thereby influencing the tumorigenic potential of melanoma cells [66, 67]. PI3Ks are classified based on substrate specificity and structure, into class-I, class-II, and class-III kinases [66, 68] (Figure 3). Whereas class-I PI3Ks convert PIP2 into PIP3, class-II, and class-III PI3Ks use PIs to generate PI-3-P. Class-I PI3Ks are further subdivided into class-Ia and class-Ib [66, 67]. Activity of class-Ia PI3K is triggered by growth factor receptor tyrosine kinases, whereas class-Ib is activated by G protein-coupled receptors. Class-Ia PI3K is a heterodimer comprising of p85 regulatory and p110 catalytic subunits [66, 68]. At the plasma membrane class-Ia PI3Ks phosphorylate PIP2 at the 3′ position and convert it into PIP3 upon growth factor stimulation. PIP3 binds to the PH domain containing PDK1 and Akt proteins leading to recruitment to the plasma membrane. In addition to lipid kinase activity, class-I PI3Ks also exhibit protein kinase activity. The physiological relevance of this activity differs between the members of class I PI3Ks. For example, class-Ia PI3K phosphorylates insulin receptor substrate-1 (IRS-1), whereas class-Ib PI3K activates the MAPK signaling cascade [66, 68].


Therapeutic Implications of Targeting AKT Signaling in Melanoma.

Madhunapantula SV, Robertson GP - Enzyme Res (2011)

Schematic representation of PI3 kinase enzymes.  PI3 kinases are a group of enzymes involved in regulating cell growth, proliferation, differentiation, motility, and survival.  Based on structure and substrate specificity PI3 kinases have been divided into Class I (EC number: 2.7.1.153), Class II (EC number: 2.7.1.154), and Class III (2.7.1.137) enzymes.  Class I and II PI3Ks are composed of regulatory and catalytic subunits, whereas Class III contains only catalytic subunit.  Depending on the type of subunits, heteromeric Class I PI3Ks are further subdivided into Class IA and Class IB.  Whereas Class IA PI3K consists of p85 regulatory subunit and p110 catalytic subunit, the Class IB PI3K is made up of p101 regulatory subunit and p110γ catalytic subunit. Class IA PI3K is the most common PI3Ks implicated in the development of cancers.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3065045&req=5

fig3: Schematic representation of PI3 kinase enzymes. PI3 kinases are a group of enzymes involved in regulating cell growth, proliferation, differentiation, motility, and survival. Based on structure and substrate specificity PI3 kinases have been divided into Class I (EC number: 2.7.1.153), Class II (EC number: 2.7.1.154), and Class III (2.7.1.137) enzymes. Class I and II PI3Ks are composed of regulatory and catalytic subunits, whereas Class III contains only catalytic subunit. Depending on the type of subunits, heteromeric Class I PI3Ks are further subdivided into Class IA and Class IB. Whereas Class IA PI3K consists of p85 regulatory subunit and p110 catalytic subunit, the Class IB PI3K is made up of p101 regulatory subunit and p110γ catalytic subunit. Class IA PI3K is the most common PI3Ks implicated in the development of cancers.
Mentions: Phosphatidyl inositol 3 kinases (PI3Ks) are a family of intracellular lipid kinases that phosphorylate the 3′ hydroxyl group of phosphatidylinositols (Pis) and phosphoinositides [66, 67]. Activation of PI3K affects cell growth, proliferation and survival thereby influencing the tumorigenic potential of melanoma cells [66, 67]. PI3Ks are classified based on substrate specificity and structure, into class-I, class-II, and class-III kinases [66, 68] (Figure 3). Whereas class-I PI3Ks convert PIP2 into PIP3, class-II, and class-III PI3Ks use PIs to generate PI-3-P. Class-I PI3Ks are further subdivided into class-Ia and class-Ib [66, 67]. Activity of class-Ia PI3K is triggered by growth factor receptor tyrosine kinases, whereas class-Ib is activated by G protein-coupled receptors. Class-Ia PI3K is a heterodimer comprising of p85 regulatory and p110 catalytic subunits [66, 68]. At the plasma membrane class-Ia PI3Ks phosphorylate PIP2 at the 3′ position and convert it into PIP3 upon growth factor stimulation. PIP3 binds to the PH domain containing PDK1 and Akt proteins leading to recruitment to the plasma membrane. In addition to lipid kinase activity, class-I PI3Ks also exhibit protein kinase activity. The physiological relevance of this activity differs between the members of class I PI3Ks. For example, class-Ia PI3K phosphorylates insulin receptor substrate-1 (IRS-1), whereas class-Ib PI3K activates the MAPK signaling cascade [66, 68].

Bottom Line: Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease.However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use.Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

ABSTRACT
Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

No MeSH data available.


Related in: MedlinePlus