Arl2

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ADP-ribosylation factor like protein 2 (ARL2), a small GTP-binding protein with a relative molecular mass of 20,800, is an ARL member of the ARF (ADP-ribosylation factor) family. ARL2 is expressed in almost all mammalian tissues and is highest in neural tissue. ARL2 binds to tubulin cofactor D (TBCD) in the cytoplasm in the form of ARL2-GDP, regulating microtubule dynamics. ARL2-GTP forms a complex with the ARL2 binding factor (BART) into the mitochondria to maintain mitochondrial morphology, movement, ATP levels, and mitochondrial fusion.

Figure 1. A revised scheme for tubulin factors and Arl2 as a chaperone multi-subunit machine in regulating soluble αβ-tubulin. (Stanley, et al, 2015)

Structural Features and Functions of ARL2

ARL2 is highly conserved in eukaryotes and has close structural homology, such as Drosophila melanogaster (80% identity) and Caenorhabditis elegans (60% identity). ARL2 and ARF have the original structure of the RAS superfamily protein in the three-dimensional structure, that is, five α-helices surround the six-strand β-fold. However, unlike ARF, the N-terminal helix structure of ARL2 may be more flexible, and the exposure of the helix structure does not depend on the binding state of GDP and GTP and can be combined with the cell membrane. At the same time, the N-terminal of ARL2 also has a glycine myristoylation site of ARF protein, but it does not exhibit myristoylation. Therefore, ARL2 does not activate phospholipase D and cholera toxin-like ARF proteins. These biochemical and genetic data indicate that ARL2 has many unique biological functions.

As a GTPase, ARL2 rapidly binds to GTP or GDP molecules and does not rely on the help of lipids and detergents to perform different functions in different states combined with GTP or GDP. Studies have shown that overexpression of TBCD in cultured cells results in the destruction of tubulin heterodimers and microtubules. ARL2 binds to TBCD in the form of ARL2-GDP, preventing its destruction of tubulin and microtubules and protecting the integrity of microtubules. In view of the close relationship between ARL2 and microtubules, the application of nocodazole to treat CHO cells destroys microtubules, and it is found that ARL2 is still present in the centrosome and does not depend on microtubules. This indicates that ARL2 is involved in maintaining the integrity of the centrosome. Approximately 10% of ARL2 in the cytoplasm is located in the mitochondria. ARL2-GTP and BART (ARL2 binding protein) bind to mitochondria with high affinity, regulate mitochondrial morphology, movement, and mitochondrial fusion. In addition, ARL2 enhances BART interaction with STAT3 and promotes STAT3 nuclear translocation.

Mechanism of Action of ARL2 in Tumors

In tumors, ARL2 acts as an oncogene or tumor suppressor gene and becomes a therapeutic target. Hass et al found that ARL2 is up-regulated in hepatocellular carcinoma and is associated with prognosis. Peng et al found that in cervical cancer, ARL2 expression is higher than in adjacent tissues. Silencing ARL2 can inhibit the proliferation and invasion of cervical cancer cells. In breast cancer, ARL2 overexpression can reduce the invasiveness of breast cancer cells and improve the chemosensitivity of tumors. Sexuality, promotes apoptosis, indicating that ARL2 is a tumor suppressor gene for breast cancer.

ARL2 can promote the proliferation and invasion of cervical cancer and pancreatic cancer cells, but inhibit the progression of breast cancer cells, promote apoptosis and enhance chemosensitivity. ARL2 plays the role of oncogene or tumor suppressor gene in tumors. The intervention of ARL2 function will achieve the anti-tumor effect, but the specific mechanism of action is not very clear.

Combined with the function of ARL2, it is possible to regulate the biological functions of tumors through the following aspects: (1) Microtubules: As a core molecule in the process of microtubule synthesis, changing the content of ARL2 affects microtubule dynamics, cell cycle and the sensitivity of chemotherapy drugs to achieve anti-tumor purposes. (2) Mitochondria: Newman et al found that ARL2 regulates mitochondrial fusion and decreases ARL2 content leading to mitochondrial dysfunction. In bladder cancer, knockdown of ARL2 results in decreased ATP production and mitochondrial membrane potential, and inhibits cell growth activity, suggesting that ARL2 down-regulates mitochondrial function in bladder cancer cells. (3) Participation in signal transduction: both ARL2 and ARL3 can bind to phosphodiesterase δ (PDEδ), regulate the transport of farnesylated substances such as KRAS, accumulate KRAS in the inner membrane of cells, and participate in downstream signaling pathway transduction. Zhang et al. showed that there are RAS mutations or excessive activation in various tumors, for example, KRAS-4B appears in about 21% of human tumors. In addition, ARL2 enhances BART interaction with STAT3 and promotes STAT3 nuclear translocation and transcriptional activity. Given the importance of RAS and STAT3 in tumors, ARL2 may influence the phenotype of tumor cells through RAS and STAT3 signaling pathways. (4) GTPase-activating protein (GAP): GAP is a GTPase-activating protein. Ivanova et al. found that GAP can bind to the GTP-bound RAS superfamily protein, accelerate GTP hydrolysis, and affect downstream signaling pathways. ELMOD2 is a GAP of ARL2, and Newman et al. found that ARL2 in mitochondria requires the involvement of ELMOD2 to regulate mitochondrial fusion and movement. At present, a variety of RAS GAPs such as NF1, DAB2IP and small molecule inhibitors that inhibit GAP activity, such as CCG-63802, have been intensively studied to block tumors by blocking the RAS signaling pathway.