{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIK3CG, which encodes the class IB catalytic subunit p110γ, plays a central role in mediating immune cell responses. In neutrophils, p110γ is essential for the early-phase activation of phosphatidylinositol 3‐kinase (PI3K) that drives reactive oxygen species production, cell polarization, and directional migration in response to chemoattractants. In addition, activation of p110γ downstream of multiple receptor types—including G protein–coupled receptors, receptor tyrosine kinases, and Toll-like/IL-1 receptors—facilitates inside‐out integrin activation and myeloid cell invasion into tumors. Moreover, hypoxic tumor cells can secrete exosomes enriched with miR‑301a‑3p that engage the PTEN/PI3Kγ signaling pathway to drive macrophage polarization toward an M2 phenotype, thereby promoting cancer cell invasion and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in immune and inflammatory responses, p110γ contributes directly to oncogenic processes and cardiovascular regulation. In cultured cells, the non‑α isoforms of class I PI3K—including p110γ—are inherently capable of inducing cellular transformation in a Ras‑dependent manner, suggesting that wild‑type p110γ possesses oncogenic potential. Complementary genetic studies have also associated variations within PIK3CG with altered platelet aggregation responses, implicating p110γ in thrombosis and the regulation of cardiovascular function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn nonimmune contexts, p110γ also modulates signaling in cardiac and neuronal settings. In cardiomyocytes, p110γ functions as a signal scaffold by anchoring protein kinase A to regulate β‑adrenergic receptor internalization and downstream phosphodiesterase activity, a mechanism that contributes to contractile dysfunction in heart failure. Moreover, in astrocytoma cells, activation of the CB1 cannabinoid receptor triggers a class IB PI3K–dependent cascade that leads to ERK activation and enhanced cell survival, revealing a potential neuroprotective role for p110γ."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alison M Condliffe, Keith Davidson, Karen E Anderson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2005-03-0944"}], "href": "https://doi.org/10.1182/blood-2005-03-0944"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15878979"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15878979"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "G John Ferguson, Laura Milne, Suhasini Kulkarni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI(3)Kgamma has an important context-dependent role in neutrophil chemokinesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb1517"}], "href": "https://doi.org/10.1038/ncb1517"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17173040"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17173040"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Bryan Heit, Lixin Liu, Pina Colarusso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI3K accelerates, but is not required for, neutrophil chemotaxis to fMLP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.020412"}], "href": "https://doi.org/10.1242/jcs.020412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18187452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18187452"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Michael C Schmid, Christie J Avraamides, Holly C Dippold, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.04.016"}], "href": "https://doi.org/10.1016/j.ccr.2011.04.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21665146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21665146"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xiaofeng Wang, Guangtao Luo, Kundong Zhang, et al. 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