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p110δ PI3 kinase pathway: emerging roles in cancer.

Tzenaki N, Papakonstanti EA - Front Oncol (2013)

Bottom Line: A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies.Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells.Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, University of Crete Heraklion, Greece.

ABSTRACT
Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p110α, p110β, and p110δ which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110α isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110β or p110δ have been reported. Unlike p110α and p110β which are ubiquitously expressed, p110δ is highly enriched in leukocytes and thus the p110δ PI3K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110δ PI3K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies. Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling. In this review, we summarize our understanding of the p110δ PI3K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110δ in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110δ PI3K in cancer.

No MeSH data available.


Related in: MedlinePlus

Simplified scheme showing the critical role of Class IA PI3Ks in multiple cellular functions. Upon PI3Ks activation, PI(3,4,5)P3 is produced and recruits Akt at the cell membrane where it becomes phosphorylated at The308 by PDK1 and at Ser473 by mTORC2. Fully activated Akt phosphorylates a variety of effector molecules including the TSC1/2, BAD, FOXO, GSK-3β, and p27 which then control cell growth, metabolism, survival, cell cycle, or migration. PI(3,4,5)P3 also activates GEFs or GAPs which then regulate the activity of small GTPases controlling cell motility. The PI(3,4,5)P3 levels produced by PI3Ks are regulated by the PTEN phosphatase which counteracts the PI3K reaction by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 yielding back PI(4,5)P2.
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Figure 2: Simplified scheme showing the critical role of Class IA PI3Ks in multiple cellular functions. Upon PI3Ks activation, PI(3,4,5)P3 is produced and recruits Akt at the cell membrane where it becomes phosphorylated at The308 by PDK1 and at Ser473 by mTORC2. Fully activated Akt phosphorylates a variety of effector molecules including the TSC1/2, BAD, FOXO, GSK-3β, and p27 which then control cell growth, metabolism, survival, cell cycle, or migration. PI(3,4,5)P3 also activates GEFs or GAPs which then regulate the activity of small GTPases controlling cell motility. The PI(3,4,5)P3 levels produced by PI3Ks are regulated by the PTEN phosphatase which counteracts the PI3K reaction by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 yielding back PI(4,5)P2.

Mentions: Activation of tyrosine kinase receptors by growth factors recruits class IA PI3 kinases to the cell membrane. Activated growth factor receptors possess phosphorylated Tyr-X-X-Met motifs in which bind with high affinity the regulatory subunits of class IA PI3Ks by their SH2 domains (Figure 1). In cells, activated class IA PI3Ks phosphorylate primarily the phosphatidylinositol (PI)-4,5-bisphosphate [PI(4,5)P2] yielding the product PI(3,4,5)P3 (Vanhaesebroeck et al., 2001) (Figure 2). The generation of PI(3,4,5)P3 leads to the recruitment of adaptor and effector proteins containing pleckstrin-homology (PH)-domains, including regulators of small GTPases [such as guanosine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs)] and Ser/Thr kinases (such as PDK1 and Akt/PKB), which thus become located at the plasma membrane (Klarlund et al., 1997; Krugmann et al., 2002; Welch et al., 2002; Marone et al., 2008). Small GTPases are activated (become GTP-bound) by GEFs whereas the return from their active state to an inactive state (GDP-bound) is catalyzed by GAPs (Figure 2). Cyclic activation-inactivation of the small GTPases is required for cell body to move properly (Ridley et al., 2003). PDK1, which is in an active state under basal conditions, becomes additionally activated on cell stimulation (Alessi et al., 1997a; Pullen et al., 1998; Currie et al., 1999) and phosphorylates Akt on Thr308 (Alessi et al., 1997a,b; Stokoe et al., 1997; Stephens et al., 1998). Akt is also phosphorylated on Ser473 (Alessi et al., 1996) by mTORC2 (mTOR complexed with the Rictor protein) (Sarbassov et al., 2005) (Figure 2). Full activation of Akt kinase activity requires the phosphorylation of both kinase domains of Akt (Bellacosa et al., 1998).


p110δ PI3 kinase pathway: emerging roles in cancer.

Tzenaki N, Papakonstanti EA - Front Oncol (2013)

Simplified scheme showing the critical role of Class IA PI3Ks in multiple cellular functions. Upon PI3Ks activation, PI(3,4,5)P3 is produced and recruits Akt at the cell membrane where it becomes phosphorylated at The308 by PDK1 and at Ser473 by mTORC2. Fully activated Akt phosphorylates a variety of effector molecules including the TSC1/2, BAD, FOXO, GSK-3β, and p27 which then control cell growth, metabolism, survival, cell cycle, or migration. PI(3,4,5)P3 also activates GEFs or GAPs which then regulate the activity of small GTPases controlling cell motility. The PI(3,4,5)P3 levels produced by PI3Ks are regulated by the PTEN phosphatase which counteracts the PI3K reaction by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 yielding back PI(4,5)P2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585436&req=5

Figure 2: Simplified scheme showing the critical role of Class IA PI3Ks in multiple cellular functions. Upon PI3Ks activation, PI(3,4,5)P3 is produced and recruits Akt at the cell membrane where it becomes phosphorylated at The308 by PDK1 and at Ser473 by mTORC2. Fully activated Akt phosphorylates a variety of effector molecules including the TSC1/2, BAD, FOXO, GSK-3β, and p27 which then control cell growth, metabolism, survival, cell cycle, or migration. PI(3,4,5)P3 also activates GEFs or GAPs which then regulate the activity of small GTPases controlling cell motility. The PI(3,4,5)P3 levels produced by PI3Ks are regulated by the PTEN phosphatase which counteracts the PI3K reaction by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 yielding back PI(4,5)P2.
Mentions: Activation of tyrosine kinase receptors by growth factors recruits class IA PI3 kinases to the cell membrane. Activated growth factor receptors possess phosphorylated Tyr-X-X-Met motifs in which bind with high affinity the regulatory subunits of class IA PI3Ks by their SH2 domains (Figure 1). In cells, activated class IA PI3Ks phosphorylate primarily the phosphatidylinositol (PI)-4,5-bisphosphate [PI(4,5)P2] yielding the product PI(3,4,5)P3 (Vanhaesebroeck et al., 2001) (Figure 2). The generation of PI(3,4,5)P3 leads to the recruitment of adaptor and effector proteins containing pleckstrin-homology (PH)-domains, including regulators of small GTPases [such as guanosine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs)] and Ser/Thr kinases (such as PDK1 and Akt/PKB), which thus become located at the plasma membrane (Klarlund et al., 1997; Krugmann et al., 2002; Welch et al., 2002; Marone et al., 2008). Small GTPases are activated (become GTP-bound) by GEFs whereas the return from their active state to an inactive state (GDP-bound) is catalyzed by GAPs (Figure 2). Cyclic activation-inactivation of the small GTPases is required for cell body to move properly (Ridley et al., 2003). PDK1, which is in an active state under basal conditions, becomes additionally activated on cell stimulation (Alessi et al., 1997a; Pullen et al., 1998; Currie et al., 1999) and phosphorylates Akt on Thr308 (Alessi et al., 1997a,b; Stokoe et al., 1997; Stephens et al., 1998). Akt is also phosphorylated on Ser473 (Alessi et al., 1996) by mTORC2 (mTOR complexed with the Rictor protein) (Sarbassov et al., 2005) (Figure 2). Full activation of Akt kinase activity requires the phosphorylation of both kinase domains of Akt (Bellacosa et al., 1998).

Bottom Line: A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies.Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells.Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, University of Crete Heraklion, Greece.

ABSTRACT
Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p110α, p110β, and p110δ which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110α isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110β or p110δ have been reported. Unlike p110α and p110β which are ubiquitously expressed, p110δ is highly enriched in leukocytes and thus the p110δ PI3K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110δ PI3K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies. Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling. In this review, we summarize our understanding of the p110δ PI3K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110δ in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110δ PI3K in cancer.

No MeSH data available.


Related in: MedlinePlus