{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hormonally up‐regulated neu‐associated kinase (HUNK), a serine/threonine protein kinase related to the SNF1/AMPK family, has emerged as an important regulator in cancer cell survival, tumor progression, and metastasis. In breast cancer models, HUNK appears to have context‐dependent roles. In basal breast cancers, reconstitution of HUNK reduces cell motility and metastasis by sustaining the phosphorylation (and consequent inactivation) of cofilin‐1, thereby impairing actin polymerization through interference with protein phosphatase 2A binding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Conversely, in models driven by oncogenes such as c‑myc and HER2/neu, HUNK is required for both primary tumor formation and metastasis; its kinase activity is essential to restore migration and invasion capacities in deficient tumor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In these settings, HUNK supports cell survival by mediating downstream effects of the Akt pathway, including suppression of c‑myc expression and downregulation of cell cycle inhibitor p27, thus counterbalancing proapoptotic signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Additionally, HUNK directly phosphorylates targets involved in metastatic progression; for instance, phosphorylation of the epidermal growth factor receptor (EGFR) at threonine 654 enhances receptor stability and activates downstream signals that promote epithelial-to-mesenchymal transition and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Other substrates of HUNK include ITM2A, whose phosphorylation on threonine 35 links HUNK to the regulation of autophagy and cell proliferation in breast cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond its roles in tumor biology, HUNK is expressed in other tissues such as the kidney, where it modulates responses to angiotensin II by affecting gene transcription and cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In HER2-positive breast cancers, HUNK expression is maintained even in the context of resistance to targeted HER2 inhibitors, and its prosurvival function through the regulation of apoptotic and autophagy pathways marks it as a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, recent studies further consolidate the role of HUNK as a metastasis-promoting kinase whose activity underlies key processes of tumor cell invasion and survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Miguel Quintela-Fandino, Enrico Arpaia, Dirk Brenner, et al. 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