Limits...
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 Akt kinases (EC number: 2.7.11.1).  Akt, also known as protein kinase B, is a serine, threonine protein kinase implicated in the development and chemotherapeutic resistance of cancers.  Although the three isoforms, Akt1, Akt2, and Akt3, share high degree of structural homology in terms or domain (PH, catalytic, and regulatory) architecture, they exhibit variations in some of the key amino acid residues and cellular functions.  Domain organization and key phosphorylation site are represented.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3065045&req=5

fig4: Schematic representation of Akt kinases (EC number: 2.7.11.1). Akt, also known as protein kinase B, is a serine, threonine protein kinase implicated in the development and chemotherapeutic resistance of cancers. Although the three isoforms, Akt1, Akt2, and Akt3, share high degree of structural homology in terms or domain (PH, catalytic, and regulatory) architecture, they exhibit variations in some of the key amino acid residues and cellular functions. Domain organization and key phosphorylation site are represented.

Mentions: Akt, also known as protein kinase B, is a member of AGC family kinases and has three isoforms Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ) [71, 78] (Figure 4). These three isoforms share >80% homology and contain pleckstrin homology (PH), catalytic and regulatory domains [70, 71, 78–84]. The N-terminal PH domain spans amino acids 1 to 107, mediating protein-protein and protein-lipid interactions [85, 86], whereas the central catalytic domain (CD) contains a key phosphorylation residue T305 [87, 88]. The carboxy terminal regulatory domain (RD), also referred as hydrophobic motif (HM), contains a second phosphorylation site serine (S472), whose phosphorylation is required for complete activation of this kinase. Other possible phosphorylation sites may also be important, and research in this area continues [89]. In one study it has been shown that the E40K mutation enhances the enzymatic activity of Akt3 in melanomas [21, 46]. Splice variants of Akt3 lacking serine 472 have been identified but the significance of this form of the protein remains unknown [90, 91].


Therapeutic Implications of Targeting AKT Signaling in Melanoma.

Madhunapantula SV, Robertson GP - Enzyme Res (2011)

Schematic representation of Akt kinases (EC number: 2.7.11.1).  Akt, also known as protein kinase B, is a serine, threonine protein kinase implicated in the development and chemotherapeutic resistance of cancers.  Although the three isoforms, Akt1, Akt2, and Akt3, share high degree of structural homology in terms or domain (PH, catalytic, and regulatory) architecture, they exhibit variations in some of the key amino acid residues and cellular functions.  Domain organization and key phosphorylation site are represented.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3065045&req=5

fig4: Schematic representation of Akt kinases (EC number: 2.7.11.1). Akt, also known as protein kinase B, is a serine, threonine protein kinase implicated in the development and chemotherapeutic resistance of cancers. Although the three isoforms, Akt1, Akt2, and Akt3, share high degree of structural homology in terms or domain (PH, catalytic, and regulatory) architecture, they exhibit variations in some of the key amino acid residues and cellular functions. Domain organization and key phosphorylation site are represented.
Mentions: Akt, also known as protein kinase B, is a member of AGC family kinases and has three isoforms Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ) [71, 78] (Figure 4). These three isoforms share >80% homology and contain pleckstrin homology (PH), catalytic and regulatory domains [70, 71, 78–84]. The N-terminal PH domain spans amino acids 1 to 107, mediating protein-protein and protein-lipid interactions [85, 86], whereas the central catalytic domain (CD) contains a key phosphorylation residue T305 [87, 88]. The carboxy terminal regulatory domain (RD), also referred as hydrophobic motif (HM), contains a second phosphorylation site serine (S472), whose phosphorylation is required for complete activation of this kinase. Other possible phosphorylation sites may also be important, and research in this area continues [89]. In one study it has been shown that the E40K mutation enhances the enzymatic activity of Akt3 in melanomas [21, 46]. Splice variants of Akt3 lacking serine 472 have been identified but the significance of this form of the protein remains unknown [90, 91].

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