Limits...
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

p110δ PI3K pathway in B cells. Engagement of BCRs by antigen induces the phosphorylation of ITAMs in the cytoplasmic tails of Ig-α and Ig-β by Lyn leading to recruitment and activation of Syk via ITAMs and to initiation of downstream signaling cascade. Tyrosine phosphorylation of the co-receptor CD19 and BCAP recruits p110δ PI3K through SH2 interactions leading to production of PI(3,4,5)P3 which recruits PH-domain containing proteins such as Akt, Btk, and PLCγ2. Akt controls the activity of multiple signaling molecules and pathways such as the mTORC1, GSK-3, and the NF-kB pathway. Btk phosphorylates and activates PLCγ2 which then catalyzes the hydrolysis of PI(4,5)P2 yielding I(3,4,5)P3 and diacylglycerol (DAG). I(3,4,5)P3 initiates Ca2+ mobilization and DAG induces the activation of protein kinase C (PKC) isoforms. The p110δ PI3K also functions downstream of the cytokine receptors BAFFR and IL6R, which are activated by BAFF and IL-6, respectively, derived from lymphoid stromal cells, and downstream of the IL4R which is activated by IL-4 derived from T cells. Chemokine receptors (CXCR5) and co-stimulatory receptors (CD40, TLRs) also induce the activation of p110δ PI3K in B cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3585436&req=5

Figure 3: p110δ PI3K pathway in B cells. Engagement of BCRs by antigen induces the phosphorylation of ITAMs in the cytoplasmic tails of Ig-α and Ig-β by Lyn leading to recruitment and activation of Syk via ITAMs and to initiation of downstream signaling cascade. Tyrosine phosphorylation of the co-receptor CD19 and BCAP recruits p110δ PI3K through SH2 interactions leading to production of PI(3,4,5)P3 which recruits PH-domain containing proteins such as Akt, Btk, and PLCγ2. Akt controls the activity of multiple signaling molecules and pathways such as the mTORC1, GSK-3, and the NF-kB pathway. Btk phosphorylates and activates PLCγ2 which then catalyzes the hydrolysis of PI(4,5)P2 yielding I(3,4,5)P3 and diacylglycerol (DAG). I(3,4,5)P3 initiates Ca2+ mobilization and DAG induces the activation of protein kinase C (PKC) isoforms. The p110δ PI3K also functions downstream of the cytokine receptors BAFFR and IL6R, which are activated by BAFF and IL-6, respectively, derived from lymphoid stromal cells, and downstream of the IL4R which is activated by IL-4 derived from T cells. Chemokine receptors (CXCR5) and co-stimulatory receptors (CD40, TLRs) also induce the activation of p110δ PI3K in B cells.

Mentions: In resting B cells, the TC21 GTPase was found to recruit the p85α/p110δ PI3K to non-phosphorylated BCR immunoreceptor tyrosine-based activation motifs (ITAMs) (Delgado et al., 2009). Although this finding is not supported by the data suggesting a role of p110α in antigen-independent pre-BCR and BCR survival signals (Ramadani et al., 2010), it is possible that both p110α and p110δ are recruited to the BCR by TC21, however, this remains to be determined. Upon antigen binding to BCR, the ITAMs in the cytoplasmic tails of Ig-α and Ig-β (Reth, 1992) are tyrosine phosphorylated by Lyn leading to recruitment and activation of Syk initiating thus the downstream signaling cascade (Kurosaki et al., 1994; Beitz et al., 1999) (Figure 3). The tyrosine phosphorylation of the scaffolding proteins CD19 and B-cell adaptor protein (BCAP) creates Src-homology 2 (SH2)-binding domains which allow the binding of the SH2 domains of the p85 subunit and the recruitment of the p85/p110 complex to the cell membrane (Tuveson et al., 1993; Fujimoto et al., 2000; Okada et al., 2000; Yamazaki et al., 2002; Aiba et al., 2008) (Figure 3). Downstream of PI3K, the BCR signaling pathways include the activation of Akt which then regulates the GSK-3, mTOR, and NF-kB pathway as well as the activation of Bruton's tyrosine kinase (Btk), which then induces the activation of phospholypase C-γ (Spaargaren et al., 2003; Fruman, 2004) (Figure 3). PLCγ is an enzyme that catalyzes the hydrolysis of PI(4,5)P2 to generate the second messengers inositol 1,4,5-trisphosphate [I(1,4,5)P3] and diacylglycerol (DAG) that regulate the reorganization of cytoskeleton and cell adhesion by inducing an increase in intracellular free-calcium levels and the activation of multiple protein kinase C (PKC) isoforms (Figure 3) and downstream signaling molecules (Papakonstanti et al., 2000; Fruman, 2004). The p110δ PI3K signaling pathway is also activated by cytokines like BAFF and IL6 (Patke et al., 2006; Henley et al., 2008) and chemokines like CXCL13 (Reif et al., 2004) derived from lymphoid stromal cells, by cytokines like IL-4 derived from T cells (Bilancio et al., 2006) and by co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs) (Arron et al., 2001; Ni et al., 2012; So and Fruman, 2012; Troutman et al., 2012) (Figure 3). The mechanism that links the activation of p110δ to G protein-coupled chemokine receptors (such as the CXCR5) is not currently known. That p110δ PI3K mediates the effects of multiple receptors on B cells is consistent with substantial evidence documenting a central role of this enzyme in B cell development and activation (Okkenhaug and Fruman, 2010).


p110δ PI3 kinase pathway: emerging roles in cancer.

Tzenaki N, Papakonstanti EA - Front Oncol (2013)

p110δ PI3K pathway in B cells. Engagement of BCRs by antigen induces the phosphorylation of ITAMs in the cytoplasmic tails of Ig-α and Ig-β by Lyn leading to recruitment and activation of Syk via ITAMs and to initiation of downstream signaling cascade. Tyrosine phosphorylation of the co-receptor CD19 and BCAP recruits p110δ PI3K through SH2 interactions leading to production of PI(3,4,5)P3 which recruits PH-domain containing proteins such as Akt, Btk, and PLCγ2. Akt controls the activity of multiple signaling molecules and pathways such as the mTORC1, GSK-3, and the NF-kB pathway. Btk phosphorylates and activates PLCγ2 which then catalyzes the hydrolysis of PI(4,5)P2 yielding I(3,4,5)P3 and diacylglycerol (DAG). I(3,4,5)P3 initiates Ca2+ mobilization and DAG induces the activation of protein kinase C (PKC) isoforms. The p110δ PI3K also functions downstream of the cytokine receptors BAFFR and IL6R, which are activated by BAFF and IL-6, respectively, derived from lymphoid stromal cells, and downstream of the IL4R which is activated by IL-4 derived from T cells. Chemokine receptors (CXCR5) and co-stimulatory receptors (CD40, TLRs) also induce the activation of p110δ PI3K in B cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: p110δ PI3K pathway in B cells. Engagement of BCRs by antigen induces the phosphorylation of ITAMs in the cytoplasmic tails of Ig-α and Ig-β by Lyn leading to recruitment and activation of Syk via ITAMs and to initiation of downstream signaling cascade. Tyrosine phosphorylation of the co-receptor CD19 and BCAP recruits p110δ PI3K through SH2 interactions leading to production of PI(3,4,5)P3 which recruits PH-domain containing proteins such as Akt, Btk, and PLCγ2. Akt controls the activity of multiple signaling molecules and pathways such as the mTORC1, GSK-3, and the NF-kB pathway. Btk phosphorylates and activates PLCγ2 which then catalyzes the hydrolysis of PI(4,5)P2 yielding I(3,4,5)P3 and diacylglycerol (DAG). I(3,4,5)P3 initiates Ca2+ mobilization and DAG induces the activation of protein kinase C (PKC) isoforms. The p110δ PI3K also functions downstream of the cytokine receptors BAFFR and IL6R, which are activated by BAFF and IL-6, respectively, derived from lymphoid stromal cells, and downstream of the IL4R which is activated by IL-4 derived from T cells. Chemokine receptors (CXCR5) and co-stimulatory receptors (CD40, TLRs) also induce the activation of p110δ PI3K in B cells.
Mentions: In resting B cells, the TC21 GTPase was found to recruit the p85α/p110δ PI3K to non-phosphorylated BCR immunoreceptor tyrosine-based activation motifs (ITAMs) (Delgado et al., 2009). Although this finding is not supported by the data suggesting a role of p110α in antigen-independent pre-BCR and BCR survival signals (Ramadani et al., 2010), it is possible that both p110α and p110δ are recruited to the BCR by TC21, however, this remains to be determined. Upon antigen binding to BCR, the ITAMs in the cytoplasmic tails of Ig-α and Ig-β (Reth, 1992) are tyrosine phosphorylated by Lyn leading to recruitment and activation of Syk initiating thus the downstream signaling cascade (Kurosaki et al., 1994; Beitz et al., 1999) (Figure 3). The tyrosine phosphorylation of the scaffolding proteins CD19 and B-cell adaptor protein (BCAP) creates Src-homology 2 (SH2)-binding domains which allow the binding of the SH2 domains of the p85 subunit and the recruitment of the p85/p110 complex to the cell membrane (Tuveson et al., 1993; Fujimoto et al., 2000; Okada et al., 2000; Yamazaki et al., 2002; Aiba et al., 2008) (Figure 3). Downstream of PI3K, the BCR signaling pathways include the activation of Akt which then regulates the GSK-3, mTOR, and NF-kB pathway as well as the activation of Bruton's tyrosine kinase (Btk), which then induces the activation of phospholypase C-γ (Spaargaren et al., 2003; Fruman, 2004) (Figure 3). PLCγ is an enzyme that catalyzes the hydrolysis of PI(4,5)P2 to generate the second messengers inositol 1,4,5-trisphosphate [I(1,4,5)P3] and diacylglycerol (DAG) that regulate the reorganization of cytoskeleton and cell adhesion by inducing an increase in intracellular free-calcium levels and the activation of multiple protein kinase C (PKC) isoforms (Figure 3) and downstream signaling molecules (Papakonstanti et al., 2000; Fruman, 2004). The p110δ PI3K signaling pathway is also activated by cytokines like BAFF and IL6 (Patke et al., 2006; Henley et al., 2008) and chemokines like CXCL13 (Reif et al., 2004) derived from lymphoid stromal cells, by cytokines like IL-4 derived from T cells (Bilancio et al., 2006) and by co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs) (Arron et al., 2001; Ni et al., 2012; So and Fruman, 2012; Troutman et al., 2012) (Figure 3). The mechanism that links the activation of p110δ to G protein-coupled chemokine receptors (such as the CXCR5) is not currently known. That p110δ PI3K mediates the effects of multiple receptors on B cells is consistent with substantial evidence documenting a central role of this enzyme in B cell development and activation (Okkenhaug and Fruman, 2010).

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