Alternative titles; symbols
HGNC Approved Gene Symbol: PIK3CG
Cytogenetic location: 7q22.3 Genomic coordinates (GRCh38): 7:106,865,282-106,908,980 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.3 | Immunodeficiency 97 with autoinflammation | 619802 | Autosomal recessive | 3 |
Phosphatidylinositol 3-kinase (PIK3) activity is implicated in diverse cellular responses triggered by mammalian cell surface receptors. Stoyanov et al. (1995) noted that receptors with tyrosine kinase activity recruit heterodimeric PIK3 kinases composed of a p110 catalytic subunit and a p85 adaptor subunit (171833). Stoyanov et al. (1995) screened a human bone marrow cDNA library with primers based on the sequences of yeast and bovine PIK3 p110 subunits. They isolated a human cDNA for a novel p110 subunit, which they termed p110-gamma. The cDNA encodes a predicted 120-kD, 1,050-amino acid polypeptide with 36% identity to human p110-alpha (171834). The 5.3-kb p110-alpha transcript was detectable by Northern blot in human pancreas, skeletal muscle, liver, and heart.
Stoyanov et al. (1995) found that recombinant p110-gamma did not interact with the p85 subunit in vivo, in contrast to recombinant p110-alpha. The transducin G protein subunits G-beta(t) (139380)/G-gamma(t) (189970) did, however, activate p110-gamma in vitro, and the stimulation was suppressed by G-alpha(t)-GDP (139330); G-alpha(t)-GDP could stimulate p110-gamma only in the presence of AlF(4-). In contrast, the p85-dependent p110-alpha was not similarly affected by the G protein subunits. Stoyanov et al. (1995) speculated that the p110-gamma isotype may link signaling through G protein-coupled receptors and generate phosphoinositide second messengers phosphorylated in the D-3 position.
Target ligation in natural killer (NK) cells activates a Ras (190070)-independent ERK (see ERK2; 176948) pathway that leads to NK lytic function, i.e., the movement and release of perforin (170280) or granzyme B (GZMB; 123910) to target cells. Using gene manipulation and specific inhibitors of PI3K and MEK (see MAP2K1; 176872), Jiang et al. (2000) delineated a specific pathway, PI3K--RAC1 (602048)--PAK1 (602590)--MEK--ERK, in NK cells that affects lysis. Thus, PI3K plays a pivotal role in the regulation of cytotoxicity in NK cells.
Sasaki et al. (2000) found that in humans p110-gamma protein expression was lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines. Overexpression of wildtype or kinase-dead p110-gamma in human colon cancer cells with mutations of the tumor suppressors APC (611731) and p53 (191170), or the oncogenes beta-catenin (116806) and Ki-ras, suppressed tumorigenesis. Thus, p110-gamma can block the growth of human colon cancer cells.
Niswender et al. (2001) demonstrated that systemic administration of leptin (164160) in rat activates the enzyme phosphatidylinositol-3-hydroxykinase in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevents leptin-induced anorexia. They concluded that phosphatidylinositol-3-hydroxykinase is a crucial enzyme in the signal transduction pathway that links hypothalamic leptin to reduced food intake.
Brock et al. (2003) showed that fluorescence-tagged porcine p101 (PIK3R5; 611317) and human p110-gamma interacted in transfected human embryonic kidney cells and retained the essential functions of wildtype heterodimeric PI3K-gamma. G protein-beta (see GNB1; 139380)-gamma (see GNG2; 606981) recruited PI3K-gamma from the cytosol to the membrane through interaction with the p101 subunit. Accordingly, p101 was required for G protein-mediated activation of PI3K-gamma. Membrane-targeted p110-gamma displayed basal enzymatic activity, but it was further stimulated by G-beta-gamma, even in the absence of p101. Brock et al. (2003) concluded that the noncatalytic p101 subunit of PI3K-gamma is an adaptor molecule that recruits the catalytic subunit to the plasma membrane through high-affinity interaction with G-beta-gamma. In turn, direct interaction between G-beta-gamma and membrane-attached p110-gamma contributes to final activation of the enzyme by a mechanism other than translocation.
Zhao et al. (2006) showed that electric fields, of a strength equal to those detected endogenously, direct cell migration during wound healing as a prime directional cue. Manipulation of endogenous wound electric fields affects wound healing in vivo. Electric stimulation triggers activation of Src and inositol-phospholipid signaling, which polarizes in the direction of cell migration. Notably, genetic disruption of PIK3CG decreased electric field-induced signaling and abolished directed movements of healing epithelium in response to electric signals. Deletion of the tumor suppressor phosphatase and tensin homolog (PTEN; 601728) enhanced signaling and electrotactic responses. Zhao et al. (2006) concluded that their data identified genes essential for electrical signal-induced wound healing and showed that PIK3CG and PTEN control electrotaxis.
Hawkins and Stephens (2007) gave a review of PI3K-gamma function.
Kaneda et al. (2016) showed that macrophage Pi3k-gamma controlled a critical switch between immune stimulation and suppression during inflammation and cancer in mice. Pi3k-gamma signaling through Akt and Mtor (601231) inhibited Nfkb (see 164011) activation and stimulated Cebpb (CEBPB; 189965) activation, inducing a transcriptional program that promoted immune suppression during inflammation and tumor growth. Selective inactivation of mouse macrophage Pi3k-gamma stimulated and prolonged Nfkb activation and inhibited Cebpb activation, promoting an immunostimulatory transcriptional program that restored Cd8-positive T-cell activation and cytotoxicity. Kaneda et al. (2016) proposed that therapeutic targeting of intracellular signaling pathways that regulate the switch between macrophage polarization states may control immune suppression in cancer.
Kratz et al. (2002) determined that the PIK3CG gene contains 10 exons and spans approximately 37 kb of genomic DNA.
By FISH, Sasaki et al. (2000) mapped the PIK3CG gene to 7q22.
Stumpf (2022) mapped the PIK3CG gene to chromosome 7q22.3 based on an alignment of the PIK3CG sequence (GenBank BC035683) with the genomic sequence (GRCh38).
Immunodeficiency-97 With Autoinflammation
In a 9-year-old girl of European-American descent with immunodeficiency-97 with autoinflammation (IMD97; 619802), Takeda et al. (2019) identified compound heterozygous mutations in the PIK3CG gene (601232.0001 and 601232.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Patient T cells showed almost absent expression of the PIK3CG catalytic p110-gamma protein, whereas parental cells had reduced levels. In vitro studies showed nearly abolished p110-gamma catalytic activity. Patient T cells responded poorly to TCR stimulation in vitro, and decreased AKT (164730) phosphorylation was also observed, suggesting downstream signaling defects. The myeloid cell compartment showed abnormalities, including elevated expression of proinflammatory cytokines IL12 (see 161560), IL23 (see 605580), IL1B (147720), and TNFA (191160). The authors concluded that PIK3CG deficiency reduces AKT activation and promotes a proinflammatory macrophage phenotype with increased cytokine production that leads to increased T-cell tissue accumulation. In this patient, the abnormalities were associated with reduced T(reg) cells and increased Th1-like T cells that infiltrate barrier tissues. The findings suggested a role for PI3KCG in restraining inflammation and promoting appropriate adaptive immune responses in humans.
In a 14-year-old Austrian girl with IMD97, Thian et al. (2020) identified compound heterozygous missense mutations in the PIK3CG gene (R49S, 601232.0003 and N1085S, 601232.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Both occurred at highly conserved residues and were absent from the gnomAD database. Patient-derived T cells showed impaired activation and proliferation in response to CD3+ agonists and defective PIK3CG-dependent activation via the TCR compared to controls, suggesting disruption of this signaling pathway. Decreased AKT (164730) phosphorylation was also observed. Abnormalities in NK cells, myeloid cells, and neutrophils were also present, suggesting wide disruption of immune cell function.
Exclusion Studies
Kratz et al. (2002) evaluated the PIK3CG gene as a candidate myeloid tumor suppressor gene. By FISH, they assigned the gene to a commonly deleted segment defined previously in myeloid leukemias with breakpoints within 7q22. Forty leukemias with monosomy 7 or a del(7q) were screened for PIK3CG mutations. Two patients had missense variations affecting residue 859 in the N-terminal catalytic domain of the protein. This allele was also detected in unaffected parents and in 1 of 60 control alleles; it probably represents a polymorphism. Kratz et al. (2002) concluded that PIK3CG is unlikely to act as a recessive tumor suppressor gene in myeloid leukemias with monosomy 7.
Hirsch et al. (2000), Sasaki et al. (2000), and Li et al. (2000) each independently developed mice deficient in PI3K-gamma by targeted disruption. PI3K-gamma -/- mice were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3K-gamma -/- neutrophils did not produce phosphatidylinositol 3,4,5-triphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3K-gamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model, as shown by Hirsch et al. (2000). These results demonstrated that PI3K-gamma is a crucial signaling molecule required for macrophage accumulation in inflammation. Sasaki et al. (2000) demonstrated that PI3K-gamma controls thymocyte survival and activation of mature T cells, but has no role in the development or function of B cells. PI3K-gamma-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to G protein-coupled receptor agonists and chemotactic agents. PI3K-gamma links G protein-coupled receptor stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase (see 608938), and extracellular signal-regulated kinases 1 (601795) and 2. Thus, Sasaki et al. (2000) concluded that PI3K-gamma regulates thymocyte development, T-cell activation, neutrophil migration, and the oxidative burst. Li et al. (2000) reported similar results and also found that PI3K-gamma has an important role in chemoattractant-induced superoxide production and chemotaxis and in the production of T cell-independent antigen-specific antibodies composed of the immunoglobulin-gamma light chain.
Sasaki et al. (2000) reported that genetic inactivation of the p110-gamma catalytic subunit of PI3K-gamma leads to the development of invasive colorectal adenocarcinomas in mice. However, in an erratum, they stated that additional experiments with mice showed that inactivation of this subunit 'does not in itself cause colon cancer, but may require additional factors.' Barbier et al. (2001) analyzed tissue biopsies from more than 100 PI3K-gamma-null mice at various ages and of both sexes from 2 genetic backgrounds (129/SV inbred and C57BL/SJ/129 outbred) and demonstrated no malignant transformation. They concluded that their findings were consistent with a lack of tumorigenesis in PI3K-gamma-null strains generated by 3 of 4 strategies.
Crackower et al. (2002) showed that cardiomyocyte-specific inactivation of Pten (601728) in mice resulted in hypertrophy and, unexpectedly, a dramatic decrease in cardiac contractility. Analysis of Pten/Pi3k-gamma double-mutant mice revealed that the cardiac hypertrophy and contractility defects could be genetically uncoupled. Pi3k-alpha was found to mediate the alteration in cell size, whereas Pi3k-gamma was found to act as a negative regulator of cardiac contractility. Mechanistically, Pi3k-gamma inhibited cAMP production, and hypercontractility could be reverted by blocking cAMP function. These data showed that PTEN has an important in vivo role in cardiomyocyte hypertrophy and G protein-coupled receptor signaling and identified a function for the PTEN-PI3K-gamma pathway in the modulation of heart muscle contractility.
Oudit et al. (2003) infused isoproterenol into Pi3k-gamma-null mice and found that the null mice had an attenuated cardiac hypertrophic response and markedly reduced interstitial fibrosis compared to controls. Chronic beta-adrenergic receptor stimulation triggered impaired heart functions in wildtype mice, whereas Pi3k-gamma-null mice retained their increased heart function and did not develop heart failure. Oudit et al. (2003) concluded that PI3K-gamma is critical for the induction of hypertrophy, fibrosis, and cardiac dysfunction in response to beta-adrenergic receptor stimulation in vivo.
By selective inactivation of Pten in mouse B lymphocytes and immunohistochemical analysis, Anzelon et al. (2003) detected a selective expansion of marginal zone (MZ) B and B1 cells. Pten-deficient B cells were hyperproliferative in response to mitogenic stimuli and had a lower threshold for activation through the B lymphocyte antigen receptor. Inactivation of Pten rescued germinal center, MZ B, and B1 cell formation in Cd19 (107265) -/- mice, which exhibit reduced activation of PI3K. Anzelon et al. (2003) concluded that intracellular phosphatidylinositol-3,4,5-trisphosphate has a central role in the regulation of differentiation of peripheral B-cell subsets.
Patrucco et al. (2004) reported that mice carrying a targeted mutation in the Pik3cg gene causing loss of kinase activity (Pik3cg KD/KD) displayed reduced inflammatory reactions but no alterations in cardiac contractility. cAMP levels were normal in Pik3cg KD/KD hearts, and Pik3cg-deficient mice, but not Pik3cg KD/KD mice, developed dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction. Furthermore, the data indicated that PIK3CG is an essential component of a complex controlling PDE3B (602047) phosphodiesterase-mediated cAMP destruction. Patrucco et al. (2004) concluded that cardiac PIK3CG participates in 2 distinct signaling pathways: a kinase-dependent activity that controls PKB/AKT (see 164730), as well as MAPK phosphorylation, and contributes to transverse aortic constriction-induced cardiac remodeling, and a kinase-independent activity that relies on protein interactions to regulate PDE3B activity and negatively modulates cardiac contractility.
Del Prete et al. (2004) found that dendritic cells from Pik3cg-knockout mice had reduced responses to chemokines and impaired ability to travel to lymph nodes during inflammation. Pik3cg-knockout mice were also unable to mount hypersensitivity reactions to antigens. The authors concluded that PIK3CG plays a role in dendritic cell trafficking and in activation of specific immunity.
Camps et al. (2005) used structure-based drug design to develop a potent small molecule inhibitor of PIK3CG (referred to as AS-605240). Camps et al. (2005) found that Pik3cg-null mice were protected against arthritis induced by collagen II-specific antibodies, a murine model of lymphocyte-independent rheumatoid arthritis (180300) associated with neutrophil activation. The effect was associated with impaired neutrophil chemotaxis. Treatment of wildtype mice with oral AS-605420 resulted in reduced clinical and histologic signs of collagen II-antibody-induced arthritis, similar to that seen in the Pik3cg-null mice. Oral AS-605240 also resulted in decreased joint inflammation and damage in a distinct mouse model of lymphocyte-dependent rheumatoid arthritis induced by direct collagen II injection. Camps et al. (2005) concluded that PIK3CG inhibition operates on both the neutrophil and lymphocyte arms of chemokine signaling pathways, and thus may be of therapeutic value in various chronic inflammatory diseases.
In the MRL-lpr mouse model of systemic lupus erythematosus (SLE; 152700), Barber et al. (2005) found that intraperitoneal administration of the pharmacologic PIK3CG inhibitor AS-605240 reduced CD4+ T-cell populations, reduced glomerulonephritis, and prolonged life span.
Using a preclinical mouse model system, De Henau et al. (2016) showed that the suppressive activity of infiltrating myeloid cells mediated resistance to immune checkpoint blocking (ICB) in various tumors. Pharmacologic targeting of Pi3k-gamma restored sensitivity to ICB. Pi3k-gamma targeting reshaped the tumor immune microenvironment and promoted cytotoxic T-cell-mediated tumor regression without targeting cancer cells directly. De Henau et al. (2016) proposed that combination strategies using a selective PI3K-gamma inhibitor may help overcome resistance to ICB in patients with high levels of suppressive myeloid-cell infiltration in tumors.
Takeda et al. (2019) found that Pik3cg-null mice had T-cell activation defects when exposed to pet-store mice carrying common pathogens. There was reduced T(reg) frequency, reduced levels of IgG, and increased IL12 production in macrophages. This findings were associated with increased T-cell infiltration in the gut, likely due to hyperinflammatory macrophages. The findings were similar to those observed in a human patient with IMD97 (619802) due to PIK3CG mutations.
In a 9-year-old girl of European-American descent with immunodeficiency-97 with autoinflammation (IMD97; 619802), Takeda et al. (2019) identified compound heterozygous mutations in the PIK3CG gene: a 1-bp deletion (c.2944delA) resulting in a frameshift (Arg982fs), and a c.3062G-C transversion, resulting in an arg1021-to-pro (R1021P; 601232.0002) substitution at a conserved residue in the kinase domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Patient cells showed decreased PIK3CG mRNA levels, suggesting that the frameshift mutation causes nonsense-mediated mRNA decay. Patient T cells showed almost absent expression of the catalytic p110-gamma protein, whereas parental cells had reduced levels. In vitro studies showed that the R1021P protein nearly abolished p110-gamma catalytic activity. Patient T cells responded poorly to TCR stimulation in vitro; decreased AKT (164730) phosphorylation was also observed, suggesting downstream signaling defects. The myeloid cell compartment showed abnormalities, including elevated expression of proinflammatory cytokines IL12 (see 161560), IL23 (see 605580), IL1B (147720), and TNFA (191160). The authors concluded that PIK3CG deficiency reduces AKT activation and promotes a proinflammatory macrophage phenotype with increased cytokine production that leads to increased T-cell tissue accumulation. In this patient, the abnormalities were associated with reduced T(reg) cells and increased Th1-like T cells that infiltrate barrier tissues. In addition to systemic inflammation and autoimmune cytopenias, the patient hypogammaglobulinemia and recurrent infections.
For discussion of the c.3062G-C transversion in the PIK3CG gene, resulting in an arg1021-to-pro (R1021P) substitution, that was found in compound heterozygous state in a patient with immunodeficiency-97 with autoinflammation (IMD97; 619802) by Takeda et al. (2019), see 601232.0001.
In a 14-year-old Austrian girl with immunodeficiency-97 with autoinflammation (IMD97; 619802), Thian et al. (2020) identified compound heterozygous missense mutations in the PIK3CG gene: a c.145C-A transversion resulting in an arg49-to-ser (R49S) substitution in the adaptor binding domain, and a c.3254A-G transition, resulting in an asn1085-to-ser (N1085S; 601232.0002) substitution near the end of the kinase domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were each inherited from an unaffected parent. Both occurred at highly conserved residues and were absent from the gnomAD database. There were normal levels of the PIK3CG p110-gamma protein in patient T cells. Patient-derived T cells showed impaired activation and proliferation in response to CD3+ agonists and defective PIK3CG-dependent activation via the TCR compared to controls, suggesting disruption of this signaling pathway. Decreased AKT (164730) phosphorylation was also observed. Similar signaling abnormalities occurred in PIK3CG-null cells in vitro. Expression of wildtype PIK3CG in patient cells and in PIK3CG-null cells restored these defects in vitro, but neither R49S nor N1085S was able to rescue the phenotype, indicating that both mutations result in loss of function. Abnormalities in NK cells, myeloid cells, and neutrophils were also present. Patient-derived B cells showed intact proliferation and class switch recombination upon stimulation. The patient had significant systemic inflammation, but did not have recurrent serious infections.
For discussion of the c.3254A-G transition in the PIK3CG gene, resulting in an asn1085-to-ser (N1085S) substitution, that was found in compound heterozygous state in a patient with immunodeficiency-97 with autoinflammation (IMD97; 619802) by Thian et al. (2020), see 601232.0003.
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