{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSH3BP5, also known as Sab, functions as a critical mitochondrial scaffold protein that modulates stress‐activated MAPK signaling. It directly interacts with c‐Jun N-terminal kinase (JNK) and related kinases, serving as a docking site via its kinase interaction motifs (KIMs) to influence mitochondrial function. In hepatocytes, for example, its association with JNK contributes to palmitic acid-induced lipotoxicity, oxidative stress, and cell death, while studies have also revealed that SAPK3 phosphorylates Sab, indicating overlapping substrate recognition between JNK and its homologues. Moreover, in neuronal cells, upregulation of SH3BP5—induced by the neuroprotective peptide Humanin—leads to direct inhibition of JNK activity, thereby attenuating Alzheimer disease-related toxicity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, SH3BP5 plays multifaceted roles that appear context-dependent. Its expression is associated with poor clinical features in several malignancies. In diffuse large B-cell lymphoma, SH3BP5 is frequently expressed in aggressive subtypes and correlates with unfavorable patient outcomes. Similarly, in ovarian cancer cells, higher levels of mitochondrial Sab correspond to enhanced JNK activation and promotion of apoptotic priming, rendering cells more chemosensitive, whereas its suppression contributes to chemoresistance. Furthermore, in acute myeloid leukemia, elevated SH3BP5 expression supports cellular survival through the activation of JNK and downstream phosphorylation of pro-apoptotic proteins, with its knockdown inducing apoptosis. In lung cancer, m6A-dependent regulation of SH3BP5 mRNA stability has been linked to suppressed cell invasion, suggesting that it may function as a molecular brake on metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in stress signaling and cancer biology, SH3BP5 also functions as a guanine nucleotide exchange factor (GEF) for Rab11 proteins, thereby regulating epithelial cell polarity and lumen formation. Its activity in this capacity is tightly controlled by upstream regulators, such as Tankyrase and the E3 ligase RNF146, which modulate Rab11a activation through inhibition or restoration of SH3BP5 protein levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Naomi W Court, Ivana Kuo, Oonagh Quigley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of the mitochondrial protein Sab by stress-activated protein kinase 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2004.04.148"}], "href": "https://doi.org/10.1016/j.bbrc.2004.04.148"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15158451"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15158451"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yuji Takeshita, Yuichi Hashimoto, Mikiro Nawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SH3-binding protein 5 mediates the neuroprotective effect of the secreted bioactive peptide humanin by inhibiting c-Jun NH2-terminal kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.469692"}], "href": "https://doi.org/10.1074/jbc.M113.469692"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23861391"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23861391"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sanda Win, Tin Aung Than, Bao Han Allison Le, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-59636-6"}], "href": "https://doi.org/10.1038/s41598-020-59636-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32066809"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32066809"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kyoko Kobayashi, Motoko Yamaguchi, Kana Miyazaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B-cell lymphoma cells and their association with clinical features."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cam4.753"}], "href": "https://doi.org/10.1002/cam4.753"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27184832"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27184832"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Iru Paudel, Sean M Hernandez, Gilda M Portalatin, et al. 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