{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nARAF is a pivotal effector in the canonical Ras‐RAF–MEK–ERK pathway. It directly activates MEK1 in response to growth factor stimulation—unlike its close relatives, ARAF shows a marked preference for MEK1 over MEK2. Its activity is tightly regulated by specific in vivo phosphorylation events within its regulatory domains and by distinct lipid‐binding properties that favor interactions with monophosphorylated phosphoinositides. These characteristics ensure that ARAF is correctly localized to particular membrane microdomains, thereby facilitating efficient downstream signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "ARAF also contributes to oncogenesis through genetic alterations and by modulating interactions within the broader RAF family. In studies of colorectal cancer, only benign germline variants were identified in ARAF"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", yet activating mutations occur in other tumor entities such as intrahepatic cholangiocarcinoma—where lesions like N217I and G322S trigger pathway activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "—and in rare cases of Langerhans cell histiocytosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, experimental analyses have underscored the importance of RAF dimerization in signal propagation, indicating that structural alterations in ARAF and its partners can significantly impact downstream MEK/ERK activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n\nBeyond its canonical kinase activity, ARAF exerts several non‐canonical functions that have profound implications for tumor cell behavior. It can inhibit apoptosis by sequestering proapoptotic molecules such as MST2, thereby promoting cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " ARAF also directly phosphorylates Smad2 in its linker region, attenuating transforming growth factor‐β signals and thus influencing mesendoderm induction and differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Additionally, it plays roles in modulating cell migration and invasion through transcriptional and splicing regulatory mechanisms—including effects on ERBB3–AKT signaling and responses to signals from Gα11—that ultimately impact metastatic potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": " Importantly, alterations in ARAF, whether through mutation or changes in its expression levels, have been associated with resistance to RAF dimer inhibitors and with shifts in the balance of signaling complexes—for instance, through stabilization of BRAF:CRAF heterodimers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "20"}]}, {"type": "t", "text": "."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "16"}, {"type": "fg_fs", "start_ref": "11", "end_ref": "13"}, {"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "X Wu, S J Noh, G Zhou, et al. 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