Hormone-upregulated neuron-related kinase (Hunk) is a protein kinase that was originally found in murine mammary glands and has been overexpressed in human epidermal growth factor receptor 2 (HER2 + +/ErbB2 +) breast cancer cell lines. And MMTV-neu-derived breast tumor cell lines. However, the physiological effects of the bulk have been elusive since its identification. Although Hunk is expected to be a serine / threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK protein kinase family, no known Hunk substrate has been found to date. Recent work has demonstrated the role of Hunk in the progression of HER2+/ErbB2+ breast cancer, including resistance to HER2/ErbB2 inhibitors, and Hunk may play a role downstream of the HER2/ErbB2 and PI3K/Akt pathways. Together, these studies show that large truffles play a vital role in promoting breast tumorigenesis, such as gene knockout by shRNA knockout or genetically engineered mouse models with MMTV-neu or Pten defects in xenograft tumor models. Transformed into a Hunk-/-background barrier to the growth of breast tumors in the body. Since most HER2+/ErbB2+ breast cancer patients have acquired resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk may simultaneously suppress tumorigenesis and may enhance the efficacy of current therapies, which It is an important aspect of drug development. Therefore, work aimed at revealing specific regulatory functions against Hunk may be helpful, which may contribute to the role of this protein kinase in tumorigenesis and drug resistance.
Introductions
Hormone-upregulated neuron-related kinase (Hunk) is a serine (Ser)/threonine (Thr) protein kinase that was found on the screen to identify mammary epithelial tumor cells derived from and derived from mouse mammary glands during development The protein kinases MMTV-neu, MMTV-wnt (int2), MMTV-myc and MMTV-ras are genetically engineered mouse models. The same year Hunk was found in the breast, mouse and human homologues of the protein kinase were cloned, and the human gene was mapped to chromosome 21q22.11. Hunk is a ~ 80 kDa protein encoded by the Hunk gene. It contains multiple homologous regions with members of the SNF1/AMPK protein kinase family, including a C-terminal flanking catalytic domain called a small region called the SNF1 homology domain (SNH1). Domain domain. The SNF1/AMPK protein kinase family has known roles in metabolism, proliferation, differentiation, survival, migration, and invasion, and is expressed in many types of cancer. However, it remains relatively unknown whether Hunk will play a role in these processes.
Intracellular functions of Hunk
To date, Hunk's intracellular functions remain elusive. Although Hunk's kinase domain is highly homologous to AMPK family protein kinases and specific to Ser/Thr residues, no consensus phosphorylation sequence or true substrate for Hunk has been identified. In contrast, most experiments evaluating Hunk protein kinase activity are directly used to determine whether Hunk's catalytically inactive mutant form will alter protein localization or protein-protein interactions.
Hunk regulates mammary gland development.
One of the earliest studies on Hunk focused on its role in mammary gland development caused by changes in pregnancy. In this study, Gardner et al. Researchers found that after early pregnancy or 17β-estradiol and progesterone treatment stimulated ovariectomized mice, a large block of large breast epithelial cells up-regulated Hunk expression. This is the first paper to show that Hunk may be regulated by ovarian hormones pregnancy. Although estrogen and progesterone have definitive roles in the etiology of breast tumorigenesis, these observations are believed to have expanded to include breast cancer, although the effects of these hormones on bulky individuals have never been evaluated. Interestingly, the over-expression of transgenic Hunk in MMTV-Hunk mice resulted in impaired alveolar development and subsequent lactation defects, and reduced proliferation and differentiation of epithelial cells in the later stages of pregnancy, suggesting that Hunk was time-sensitive to pregnancy-induced breast Changes have a regulatory effect. Since estrogen and progesterone are necessary for adolescent epithelial cell proliferation and gestational alveolar differentiation, respectively, these hormones may regulate Hunk downstream to contribute to estrogen-induced breast proliferation. However, subsequent studies in Hunk-/-mice did not report changes in proliferation during pregnancy.
Hunk and breast cancer metastasis.
Hunk has also been shown to have a role in metastasis. However, it is not clear whether Hunk is a metastasis promoting factor or metastasis inhibitor. Preliminary report by Wertheim et al. In the background of feeding MMTV-myc breast tumor models to Hunk-/-, it was shown that although Hunk is indispensable for breast tumor formation induced by the myc proto-oncogene, because MMTV-myc mice transfer these tumors to the lung Is required to contain wild and Hunk-/-mice compared to Hunk-type mice, the Hunk type is easily transferred. This study also showed that the kinase activity of Hunk is necessary for myc-induced breast tumor metastasis, such as MMTV-myc. Hunk-derived breast tumor cells expressing Hunk kinase-dead mutants showed significantly less lung metastasis in vivo than those cells expressing wild-type Hunk. In vitro migration assays confirm the observation of in vivo metastasis, as Hunk kinase activity was also found to be necessary for myc-induced breast tumor migration and invasion.
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