| First Author | Posor Y | Year | 2025 |
| Journal | Proc Natl Acad Sci U S A | Volume | 122 |
| Issue | 29 | Pages | e2423358122 |
| PubMed ID | 40674428 | Mgi Jnum | J:370019 |
| Mgi Id | MGI:8223631 | Doi | 10.1073/pnas.2423358122 |
| Citation | Posor Y, et al. (2025) Inactivation of PI3K-C2alpha deregulates cell death pathways and sensitizes to endotoxic shock. Proc Natl Acad Sci U S A 122(29):e2423358122 |
| abstractText | The organismal roles of the class II PI3K isoform PI3K-C2alpha remain poorly understood. Recent studies have found PI3K-C2alpha to promote arterial thrombosis and breast cancer metastasis, generating interest in this kinase as a drug target, with small molecule PI3K-C2alpha inhibitors now available. However, the consequences of systemic PI3K-C2alpha inactivation in the nondiseased, postnatal state are largely unknown. Here, we show that induction of genetic PI3K-C2alpha inactivation in adult mice is well tolerated, without adverse effects on normal physiology. Surprisingly, however, mice with inactive PI3K-C2alpha display strong sensitization to challenge with bacterial lipopolysaccharide (LPS), a model of endotoxic shock. This sensitization is recapitulated by vascular endothelial-specific deletion of PI3K-C2alpha. Furthermore, sensitization to LPS can be fully rescued by disabling extrinsic induction of cell death by combined caspase-8- and RIPK3 deficiency. These observations validate the tolerability of systemic PI3K-C2alpha inhibition in principle but reveal an unexpected role for PI3K-C2alpha in the regulation of extrinsic cell death pathways. |
