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. HUNK is involved in multiple biological processes, such as regulating autophagy by phosphorylating Rubicon [3], and is associated with important cellular pathways like the IL-4/IL-4R cytokine signaling pathway in the context of tumor immunity [5].

In breast cancer, HUNK is upregulated in response to oncogenic HER2/neu and Akt, and is critical for breast cancer cell survival. Inhibiting HUNK in various breast cancer models, including resistant ones, can inhibit tumorigenesis and metastasis, though HUNK alterations are infrequent [1]. In colorectal cancer (CRC), HUNK inhibits epithelial-mesenchymal transition (EMT) and metastasis by phosphorylating GEF-H1 at serine 645, which activates RhoA and phosphorylates LIMK-1/CFL-1 to stabilize F-actin [2]. Hypoxia in CRC can inhibit HUNK kinase activity, leading to upregulation of migration, invasion, and EMT markers [4]. In the intestine, Hunk-kinase negatively regulates epithelial cell proliferation. In the Apc (Min) mouse model of intestinal tumourigenesis, loss of Hunk-kinase activity reduced tumour initiation rates in the small intestine [6].

Overall, HUNK plays diverse and significant roles in cancer-related biological processes, such as cell survival, metastasis, and EMT. The use of gene knockout or conditional knockout mouse models, like the Hunk-kinase deficient mouse in intestinal studies, has been crucial in revealing HUNK's functions in specific disease areas, including breast and colorectal cancer, as well as in normal intestinal homeostasis.

References:

1. Ramos-Solis, Nicole, Dilday, Tinslee, Kritikos, Alex E, Yeh, Elizabeth S. 2022. HUNK Gene Alterations in Breast Cancer. In Biomedicines, 10, . doi:10.3390/biomedicines10123072. https://pubmed.ncbi.nlm.nih.gov/36551828/

2. Han, Xiaoqi, Jiang, Siyuan, Gu, Yinmin, Ye, Qinong, Gao, Shan. 2023. HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1. In Cell death & disease, 14, 327. doi:10.1038/s41419-023-05849-2. https://pubmed.ncbi.nlm.nih.gov/37193711/

3. Zambrano, Joelle N, Eblen, Scott T, Abt, Melissa, Muise-Helmericks, Robin, Yeh, Elizabeth S. 2019. HUNK Phosphorylates Rubicon to Support Autophagy. In International journal of molecular sciences, 20, . doi:10.3390/ijms20225813. https://pubmed.ncbi.nlm.nih.gov/31752345/

4. Jiang, Siyuan, Han, Xiaoqi, Zhao, Zidong, Duan, Liqiang, Gao, Shan. 2023. Hypoxia inhibits HUNK kinase activity to induce epithelial-mesenchymal transition. In Biochemical and biophysical research communications, 681, 271-275. doi:10.1016/j.bbrc.2023.09.074. https://pubmed.ncbi.nlm.nih.gov/37793312/

5. Ramos Solis, Nicole, Cannon, Anthony, Dilday, Tinslee, Kaplan, Mark H, Yeh, Elizabeth S. 2024. HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer. In Oncoimmunology, 13, 2364382. doi:10.1080/2162402X.2024.2364382. https://pubmed.ncbi.nlm.nih.gov/38846083/

6. Reed, Karen R, Korobko, Igor V, Ninkina, Natalia, Buchman, Vladimir, Clarke, Alan R. 2015. Hunk/Mak-v is a negative regulator of intestinal cell proliferation. In BMC cancer, 15, 110. doi:10.1186/s12885-015-1087-2. https://pubmed.ncbi.nlm.nih.gov/25881306/