{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMAPK6, also known as ERK3, is an atypical mitogen‐activated protein kinase whose regulation departs from that of its classical counterparts. Unlike conventional MAPKs, MAPK6 is inherently unstable in proliferating cells owing to intrinsic destabilization regions and non‐canonical N‐terminal ubiquitination that target it for proteasomal degradation. This rapid turnover can be modulated—for example, stabilization of MAPK6 leads to cell cycle arrest and promotes differentiation. Moreover, MAPK6 is subject to further regulation via phosphorylation: it is directly phosphorylated by kinases such as Pak2 and dephosphorylated by phosphatases like hCdc14A. In addition, MAPK6 directly interacts with cell cycle regulators including cyclin D3, suggesting a role in coordinating proliferation with differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMAPK6 also plays diverse and critical roles in cancer progression. In lung cancer cells, it phosphorylates substrates such as steroid receptor coactivator 3 (SRC-3) to promote proinvasive signaling. Its expression is upregulated by oncogenic pathways—such as those driven by BRAF and KRAS—and its levels are modulated by noncoding RNAs. For instance, the lncRNA NEAT1 acts as a competing endogenous RNA to upregulate MAPK6 via the sequestration of hsa-mir-98-5p, while LINC00649 recruits factors like TAF15 to activate MAPK6 transcription in lung squamous cell carcinoma. In addition, tumor suppressive microRNAs including miR-144-3p in cervical cancer, miR499a in hepatocellular carcinoma, and miR-653-5p in breast cancer directly target MAPK6, leading to reduced cell proliferation, migration, and invasion. Furthermore, microRNA-138–mediated modulation of MAPK6 has been implicated in regulating proliferation and apoptosis in laryngeal carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in proliferation and oncogenic signaling, MAPK6 contributes to cytoskeletal regulation and cell migration. It functions in part as a guanine nucleotide exchange factor for CDC42 and phosphorylates components of the ARP2/3 complex—such as ARP3—to promote actin polymerization and the formation of filopodia, processes that are essential for directional cell motility. Structural studies have revealed unique features of MAPK6’s ATP binding pocket compared to conventional MAPKs, providing a foundation for the development of selective inhibitors. In parallel, transcriptional regulators like ZNF671 can modulate MAPK6 expression, as observed in laryngeal squamous cell carcinoma, while altered MAPK6 expression has also been implicated in the biology of non-melanoma skin cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Philippe Coulombe, Geneviève Rodier, Stéphane Pelletier, et al. 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