CAMKK2

Official Full Name

calcium/calmodulin dependent protein kinase kinase 2

Organism

Homo sapiens

GeneID

10645

Background

The product of this gene belongs to the Serine/Threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. The major isoform of this gene plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4. Protein products of this gene also phosphorylate AMP-activated protein kinase (AMPK). This gene has its strongest expression in the brain and influences signalling cascades involved with learning and memory, neuronal differentiation and migration, neurite outgrowth, and synapse formation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. The identified isoforms differ in their ability to undergo autophosphorylation and to phosphorylate downstream kinases. [provided by RefSeq, Jul 2012]

Synonyms

CAMKK; CAMKKB;

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Detailed Information

Recent Research Progress

As a member of the CaMK family, Ca²⁺/calmodulin-dependent kinase kinase (CAMMK2) phosphorylates Ca21/CaM-dependent protein kinase 1 (CaMKI), Ca21/CaM-dependent protein kinase 4 (CaMKIV), and adenosine monophosphate activation of protein kinase (AMPK) in response to increased intracellular Ca21 (Fig. 1). Regulation of CaMKI and/or CaMKIV by CAMMK2 regulates cell cycle progression, cell motility, survival, and gene transcription. In addition, CAMMK2 also affects hypothalamus, adipocytes differentiation, energy homeostasis of macrophage function, as well as lipid and carbohydrate metabolism in the liver. It has been reported that abnormal expression of CAMMK2 was associated with a variety of cancers.

Figure 1. Schematic of the CaMK signaling pathway and pharmacological inhibitors that target each component. (Lin, et al. Hepatology, 2015)

CAMMK2 and HCC

Hepatocellular carcinoma (HCC) accounts for nearly 80% of all liver cancers and represents significant health risks. Recent studies have found that CAMMK2/CaMKIV relay is an upstream regulator of the oncogenic mammalian target of rapamycin/ribosomal protein S6 kinase, and the importance of this CAMMK2/CaMKIV axis in HCC growth is confirmed by the potent growth inhibitory effects of genetically or pharmacologically decreasing CAMMK2 activity; in summary, these findings indicate that CAMMK2 and CaMKIV may represent potential targets for hepatic cancer.

CAMMK2 and glioma

Glioma refers to a tumor originating from glial cells and is a common primary intracranial tumor. Studies have found that up-regulation of CAMMK2 in high-grade glioma samples was associated with promoter hypomethylation. Increased expression of CAMMK2 is associated with poor prognosis. By in vitro experiments, it has been demonstrated that CAMMK2 can promote cell migration, invasion and proliferation. In conclusion, the expression level of CAMMK2 can be regulated by promoter methylation. CAMMK2 may serve as a prognostic marker for gliomas and may be a potential therapeutic target for gliomas.

CAMMK2 and Gastric cancer

Gastric cancer is one of the most common malignant tumors of the gastrointestinal tract and is associated with poor prognosis. Subbannayya et al. found that CAMMK2 was 7-fold overexpressed in gastric tumor tissues. Immunohistochemical labeling of tumor tissue microarrays used to validate CAMMK2 overexpression showed that it was indeed overexpressed in 94% of gastric cancer cases. Silencing CAMMK2 with small interfering RNA (siRNA) significantly reduced cell proliferation, colony formation and invasion of gastric cancer cells. The results indicate that CAMMK2 signaling in gastric cancer via AMP-activated protein kinase (AMPK) activation suggests that CAMMK2 may be a novel therapeutic target for gastric cancer.

CAMMK2 and PCa

Prostate cancer (PCa) is the second most common malignant tumor in men worldwide. Recently, CAMMK2 was identified as a target gene for miR-224. Studies have shown that forced expression of miR-224 can inhibit PCa cell proliferation and cell cycle by regulating the expression of CAMMK2 in vitro. Furthermore, the expression level of miR-224 in PCa tissue was significantly negatively correlated with the expression level of CAMMK2 mRNA. In addition, combined low miR-224 expression and high CAMMK2 expression (miR-224-low/CAMMK2-high) was closely associated with advanced clinical stage. Furthermore, PCa patients with high expression of miR-224-low/CAMMK2-more frequently had shorter overall survival than the group with other expression patterns of two molecules. In summary, the current data provide compelling evidence that miR-224 and its target gene CAMMK2 may act synergistically on the malignant progression of PCa. The combined detection of miR-224 and CAMMK2 expression represents an effective predictor of patient prognosis and can be a novel marker that can provide additional prognostic information in PCa.

In conclusion, CAMMK2 plays an important role in the development of various cancers. Therefore, further exploration of the role of CAMMK2 in the mechanism of cancer development will provide new insights into the diagnosis and treatment of cancer.

References:

Sarah Fogarty, et al. AMPK Causes Cell Cycle Arrest in LKB1-Deficient Cells via Activation of CAMKK2. Molecular Cancer Research, 2016, 14(8): 683-695
Lin Fumin, et al. The CaMKK2/CaMKIV Relay Is an Essential Regulator of Hepatic Cancer. Hepatology, 2015, 62:505-520
Liu Daming, et al. CAMKK2, Regulated by Promoter Methylation, is a Prognostic Marker in Diffuse Gliomas. CNS Neuroscience & Therapeutics, 2016, 22: 518–524
Yashwanth S, et al. Calcium calmodulin dependent kinase kinase2 - a novel therapeutic target for gastric adenocarcinoma. Cancer Biology & Therapy, 2015, 16(2): 336-345
Hao FU, et al. MicroRNA-224 and its target CAMKK2 synergistically influence tumor progression and patient prognosis in prostate cancer. Tumor Biology, 2015, 36(3): 1983–1991

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