{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPREX2 (phosphatidylinositol‐3,4,5‐trisphosphate–dependent Rac exchange factor 2) is a guanine nucleotide exchange factor (GEF) that activates Rac GTPases, thereby propagating signals that promote cell motility, proliferation, and survival. Early biochemical and structural analyses revealed that PREX2—sharing several features with its homolog PREX1—is activated by phosphoinositides and Gβγ subunits, with its pleckstrin homology (PH) domain playing a key role in conferring substrate specificity toward Rac1 (as detailed in."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Further studies demonstrated that PREX2 physically interacts with the tumor suppressor PTEN and functions as a negative regulator of PTEN’s lipid phosphatase activity. This interaction relieves the inhibitory effect of PTEN on the phosphoinositide 3‐kinase (PI3K)/Akt pathway, thereby accelerating tumorigenic processes such as proliferation, migration, and transformation in cancers like melanoma and breast carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to genetic alterations—including recurrent truncating and point mutations that enhance its Rac‐activating function—PREX2 is subject to intricate post‐transcriptional regulation. Several studies have shown that specific microRNAs (for example, miR‑338‑3p, miR‑637, and miR‑561) directly target PREX2 mRNA, leading to its downregulation and, in turn, reactivation of PTEN and suppression of Akt signaling in malignancies such as neuroblastoma, gastric cancer, and non–small cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "18"}]}, {"type": "t", "text": " Such microRNA‐mediated regulation adds an additional layer of control over PREX2’s ability to modulate oncogenic PI3K/Akt signaling.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations have underscored the complexity and context dependency of PREX2 function. For instance, insulin stimulation induces PAK‐dependent phosphorylation of PREX2 that diminishes its association with activators—thereby curtailing Rac1 activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In hepatocellular carcinoma, interactions with metabolic regulators such as glycine N‑methyltransferase (GNMT) promote HectH9‐mediated ubiquitination and degradation of PREX2, while chemokine signaling (for example, via CXCL9) can upregulate its expression to enhance invasive behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Moreover, the variability in PREX2-driven tumor formation observed in replication studies"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "and structural insights into the interfaces of the PTEN:PREX2 complex"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "27"}]}, {"type": "t", "text": "further emphasize how both genetic mutations and microenvironmental signals (also evidenced by studies in glioblastoma) converge to modulate PREX2 function. Collectively, these findings highlight PREX2 as a multifaceted regulator whose aberrant activation—by mutation, altered expression, or disrupted interactions with PTEN and microRNAs—contributes to oncogenic signaling in a variety of human cancers.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hans Rosenfeldt, José Vázquez-Prado, J Silvio Gutkind "}, {"type": "b", "children": [{"type": "t", "text": "P-REX2, a novel PI-3-kinase sensitive Rac exchange factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2004.06.097"}], "href": "https://doi.org/10.1016/j.febslet.2004.06.097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15304342"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15304342"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sarah Donald, Kirsti Hill, Charlotte Lecureuil, et al. 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