HUNK, short for Hormonally upregulated neu-associated kinase, is a serine/threonine (S/T) protein kinase related to the adenosine monophosphate-activated protein kinase (AMPK) family [1]. It was initially discovered in the mouse mammary gland, and its name reflects the gland-specific physiology and pathology. HUNK is involved in multiple cellular processes. It phosphorylates substrates to regulate pathways such as autophagy, and it has implications in cancer-related processes like epithelial-mesenchymal transition (EMT) and metastasis [4,2,5].

In a Hunk kinase-deficient mouse model, it was shown that Hunk negatively regulates epithelial cell proliferation in the morphologically normal intestine. However, increased cell migration counteracts the increased proliferation, maintaining intestinal homeostasis. In the Apc (Min) mouse model of intestinal tumourigenesis, loss of Hunk-kinase activity reduced tumour initiation rates in the small intestine, though an increase in tumour size counteracted the impact on overall tumour burden [6]. In breast cancer models, inhibiting HUNK, including in resistant models, inhibits tumorigenesis and metastasis. HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling, promoting metastasis [1,3]. In CRC models, HUNK inhibits EMT and metastasis by phosphorylating GEF-H1 at serine 645, activating RhoA and phosphorylating LIMK-1/CFL-1 [2].

In conclusion, HUNK plays crucial roles in cell proliferation, autophagy, EMT, and metastasis in various tissues, especially in the context of cancer. The use of Hunk KO/CKO mouse models has provided valuable insights into its functions in intestinal homeostasis and tumourigenesis, as well as its role in breast cancer and CRC metastasis, highlighting its potential as a therapeutic target in these disease areas.