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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 differential activation of class IA and class IB PI3K isoforms. Class IA PI3Ks are heterodimers consisting of a 110 kDa catalytic subunit (p110α, p110β, and p110δ) in complex with a p85 regulatory subunit, of which five isoforms exist. Class IA PI3Ks are activated by growth factor and cytokine receptors or adaptor proteins (e.g., CD19/BCAP in B cells). Binding of the ligand to its receptor leads to receptor dimerization and auto-phosphorylation of tyrosines (Y) which are located in pYxxM motifs. The p85 regulatory subunits have Src-homology 2 (SH2) domains which bind to phosphorylated tyrosines in YxxM motifs recruiting thus the class IA PI3Ks to the plasma membrane where their lipid substrates are located. Class IB PI3K consists of the p110γ isoform which binds to p101 or p84 regulatory subunits. Class IB PI3K is activated by G protein-coupled receptors (GPCRs). Binding of the ligand (e.g., a chemokine) to its cognate GPCR induces the dissociation of heterotrimeric G-proteins and the Gβγ subunits interact with the class IB PI3K. Arrows with dashed lines represent activation of p110β and p110δ downstream of GPCRs and activation of p110γ downstream of tyrosine kinases by currently unknown mechanisms.
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Figure 1: Simplified scheme showing the differential activation of class IA and class IB PI3K isoforms. Class IA PI3Ks are heterodimers consisting of a 110 kDa catalytic subunit (p110α, p110β, and p110δ) in complex with a p85 regulatory subunit, of which five isoforms exist. Class IA PI3Ks are activated by growth factor and cytokine receptors or adaptor proteins (e.g., CD19/BCAP in B cells). Binding of the ligand to its receptor leads to receptor dimerization and auto-phosphorylation of tyrosines (Y) which are located in pYxxM motifs. The p85 regulatory subunits have Src-homology 2 (SH2) domains which bind to phosphorylated tyrosines in YxxM motifs recruiting thus the class IA PI3Ks to the plasma membrane where their lipid substrates are located. Class IB PI3K consists of the p110γ isoform which binds to p101 or p84 regulatory subunits. Class IB PI3K is activated by G protein-coupled receptors (GPCRs). Binding of the ligand (e.g., a chemokine) to its cognate GPCR induces the dissociation of heterotrimeric G-proteins and the Gβγ subunits interact with the class IB PI3K. Arrows with dashed lines represent activation of p110β and p110δ downstream of GPCRs and activation of p110γ downstream of tyrosine kinases by currently unknown mechanisms.

Mentions: Class I phosphoinositide-3 kinases (PI3Ks) consist of a group of enzymes that transmit signals inside cells by the production of intracellular second messenger lipid signals. PI3Ks phosphorylate inositol lipids at the 3-position of the inositol ring, generating phosphatidylinositol (PI)-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] and phosphatidyl-inositol-3,4,5-trisphosphate [PI(3,4,5)P3]. These lipids trigger signal transduction cascades that control cell division, survival, metabolism, intracellular trafficking, differentiation, re-organization of the actin cytoskeleton, and cell migration under the control of PI3Ks (Vanhaesebroeck et al., 2001; Hawkins et al., 2006; Low et al., 2010; Zwaenepoel et al., 2012). The PI3K isoforms that are activated by tyrosine kinases and G-protein coupled receptors (GPCRs) are known as class IA and IB PI3Ks, respectively (Figure 1). Class IA PI3Ks are constitutive heterodimers of a 110 kDa catalytic subunit (p110) with one of the five regulatory adaptor proteins (p85α, p55α, p50α, p85β, or p55γ, collectively called “p85s”) that recruits the p110 to intracellular locations of tyrosine kinase activation (Vanhaesebroeck et al., 1997a, 2010) (Figure 1). Mammals have genes for 3 class IA catalytic subunits designated p110α, p110β, and p110δ (Vanhaesebroeck et al., 2010) (Figure 1). p110γ is the only class IB PI3K. This kinase occurs in complex with the p101 (Stephens et al., 1997; Krugmann et al., 1999) or p84 (Suire et al., 2005; Voigt et al., 2006) adaptor protein and is activated by the Gβγ subunits of heterotrimeric G-proteins (Figure 1). However, several studies have linked the p110β and p110δ isoforms of class IA to GPCRs and the class IB p110γ to tyrosine kinases, the mechanisms though are not yet clear (Sadhu et al., 2003; Reif et al., 2004; Condliffe et al., 2005; Guillermet-Guibert et al., 2008; Durand et al., 2009; Hoellenriegel et al., 2011; Schmid et al., 2011) (Figure 1). All catalytic subunits of the class I PI3Ks contain binding domains for Ras GTPases (Figure 1) and their binding to certain Ras proteins contributes to activation (Rodriguez-Viciana et al., 1994; Jimenez et al., 2002).


p110δ PI3 kinase pathway: emerging roles in cancer.

Tzenaki N, Papakonstanti EA - Front Oncol (2013)

Simplified scheme showing the differential activation of class IA and class IB PI3K isoforms. Class IA PI3Ks are heterodimers consisting of a 110 kDa catalytic subunit (p110α, p110β, and p110δ) in complex with a p85 regulatory subunit, of which five isoforms exist. Class IA PI3Ks are activated by growth factor and cytokine receptors or adaptor proteins (e.g., CD19/BCAP in B cells). Binding of the ligand to its receptor leads to receptor dimerization and auto-phosphorylation of tyrosines (Y) which are located in pYxxM motifs. The p85 regulatory subunits have Src-homology 2 (SH2) domains which bind to phosphorylated tyrosines in YxxM motifs recruiting thus the class IA PI3Ks to the plasma membrane where their lipid substrates are located. Class IB PI3K consists of the p110γ isoform which binds to p101 or p84 regulatory subunits. Class IB PI3K is activated by G protein-coupled receptors (GPCRs). Binding of the ligand (e.g., a chemokine) to its cognate GPCR induces the dissociation of heterotrimeric G-proteins and the Gβγ subunits interact with the class IB PI3K. Arrows with dashed lines represent activation of p110β and p110δ downstream of GPCRs and activation of p110γ downstream of tyrosine kinases by currently unknown mechanisms.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Simplified scheme showing the differential activation of class IA and class IB PI3K isoforms. Class IA PI3Ks are heterodimers consisting of a 110 kDa catalytic subunit (p110α, p110β, and p110δ) in complex with a p85 regulatory subunit, of which five isoforms exist. Class IA PI3Ks are activated by growth factor and cytokine receptors or adaptor proteins (e.g., CD19/BCAP in B cells). Binding of the ligand to its receptor leads to receptor dimerization and auto-phosphorylation of tyrosines (Y) which are located in pYxxM motifs. The p85 regulatory subunits have Src-homology 2 (SH2) domains which bind to phosphorylated tyrosines in YxxM motifs recruiting thus the class IA PI3Ks to the plasma membrane where their lipid substrates are located. Class IB PI3K consists of the p110γ isoform which binds to p101 or p84 regulatory subunits. Class IB PI3K is activated by G protein-coupled receptors (GPCRs). Binding of the ligand (e.g., a chemokine) to its cognate GPCR induces the dissociation of heterotrimeric G-proteins and the Gβγ subunits interact with the class IB PI3K. Arrows with dashed lines represent activation of p110β and p110δ downstream of GPCRs and activation of p110γ downstream of tyrosine kinases by currently unknown mechanisms.
Mentions: Class I phosphoinositide-3 kinases (PI3Ks) consist of a group of enzymes that transmit signals inside cells by the production of intracellular second messenger lipid signals. PI3Ks phosphorylate inositol lipids at the 3-position of the inositol ring, generating phosphatidylinositol (PI)-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] and phosphatidyl-inositol-3,4,5-trisphosphate [PI(3,4,5)P3]. These lipids trigger signal transduction cascades that control cell division, survival, metabolism, intracellular trafficking, differentiation, re-organization of the actin cytoskeleton, and cell migration under the control of PI3Ks (Vanhaesebroeck et al., 2001; Hawkins et al., 2006; Low et al., 2010; Zwaenepoel et al., 2012). The PI3K isoforms that are activated by tyrosine kinases and G-protein coupled receptors (GPCRs) are known as class IA and IB PI3Ks, respectively (Figure 1). Class IA PI3Ks are constitutive heterodimers of a 110 kDa catalytic subunit (p110) with one of the five regulatory adaptor proteins (p85α, p55α, p50α, p85β, or p55γ, collectively called “p85s”) that recruits the p110 to intracellular locations of tyrosine kinase activation (Vanhaesebroeck et al., 1997a, 2010) (Figure 1). Mammals have genes for 3 class IA catalytic subunits designated p110α, p110β, and p110δ (Vanhaesebroeck et al., 2010) (Figure 1). p110γ is the only class IB PI3K. This kinase occurs in complex with the p101 (Stephens et al., 1997; Krugmann et al., 1999) or p84 (Suire et al., 2005; Voigt et al., 2006) adaptor protein and is activated by the Gβγ subunits of heterotrimeric G-proteins (Figure 1). However, several studies have linked the p110β and p110δ isoforms of class IA to GPCRs and the class IB p110γ to tyrosine kinases, the mechanisms though are not yet clear (Sadhu et al., 2003; Reif et al., 2004; Condliffe et al., 2005; Guillermet-Guibert et al., 2008; Durand et al., 2009; Hoellenriegel et al., 2011; Schmid et al., 2011) (Figure 1). All catalytic subunits of the class I PI3Ks contain binding domains for Ras GTPases (Figure 1) and their binding to certain Ras proteins contributes to activation (Rodriguez-Viciana et al., 1994; Jimenez et al., 2002).

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