{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n BCL‑2–associated agonist of cell death (BAD) is a proapoptotic member of the BCL‑2 family that acts as a critical molecular switch regulating cell fate. In the presence of survival signals, kinases such as Akt, ERK, and p90RSK phosphorylate BAD, which results in its sequestration by 14‑3‑3 proteins and prevents its interaction with antiapoptotic partners (e.g., BCL‑2 and BCL‑XL). This phosphorylation-dependent inactivation promotes cell survival in diverse settings, as demonstrated by FGF21‐mediated protection of cardiomyocytes through PI3K–Akt1–BAD signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and by B‑RAF–MEK signaling that phosphorylates BAD to protect melanoma cells from anoikis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Conversely, under apoptotic or stress conditions, BAD becomes dephosphorylated. For example, 7‑ketocholesterol induces a rise in intracellular Ca²⁺, activating calcineurin, which dephosphorylates BAD at key serine residues – an event that facilitates its binding to antiapoptotic BCL‑2 proteins and triggers apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, posttranslational modifications such as arginine methylation by PRMT1 can inhibit Akt‐mediated phosphorylation of BAD, thereby favoring its proapoptotic activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, the phosphorylation status of BAD has significant implications in cancer biology. Elevated levels of phosphorylated BAD have been associated with platinum resistance and poorer survival in ovarian cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while somatic mutations in the BAD gene observed in colon adenocarcinomas diminish its ability to induce cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In renal cell carcinoma, modulation of BAD phosphorylation by therapeutic agents such as anti–β₂‑microglobulin antibodies has been linked to enhanced apoptotic responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, evidence from studies investigating inflammatory and stress kinase pathways also implicates BAD as a downstream target of JNK activation in ischemia/reperfusion injury, further underscoring its importance in integrating diverse cellular signals to determine cell survival or death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight that BAD functions as an integrative node: its phosphorylation and other posttranslational modifications are pivotal in tipping the balance between survival and apoptosis in both normal physiology and in disease contexts such as cancer and ischemic injury.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shu Q Liu, Derek Roberts, Alexei Kharitonenkov, et al. 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