GAS6 Gene Editing    

GAS6 is a vitamin K-dependent cytokine that binds to a family of receptor tyrosine kinases, including Axl, Tyro3, and MerTK (TAMR family). Although GAS6 can bind all three receptors, its affinity for Axl is about 100-1000 times higher than Tyro3 and MerTK. GAS6/TAMR signaling has been shown to regulate proliferation, efferocytosis, leukocyte migration, platelet aggregation, clearance of apoptotic cells, and other biological processes. In macrophages, GAS6 has become a potent inhibitor of innate immune responses. More recently, GAS6 and Axl have been implicated in the progression of a variety of cancers, sparking interest in targeting this pathway as a potential therapeutic strategy.

Functions of GAS6 in Physiology and Pathology

GAS6 levels are elevated in inflammatory conditions such as systemic lupus erythematosus, sepsis/systemic inflammatory response syndrome, and atherosclerotic plaques in vascular smooth muscle cells. GAS6 universally exhibits anti-inflammatory effects through the downregulation of interferon γ, TNFα, interleukin-6, and intercellular adhesion molecule-1 expression, playing an important role in preserving immune homeostasis. Apart from blocking platelet activation and protecting mice from thrombosis, inhibition or deficiency of GAS6 has also been shown to prevent liver inflammation, hepatic fibrosis, and steatohepatitis but enhanced colitis-related tumorigenesis in murine models. Once secreted, GAS6 primarily binds to the TAM family receptor tyrosine on the platelet surface by the C-terminal sex hormone binding globulin (SHBG)-like domain composed of two laminin G domains. This binding triggers dimerization and autophosphorylation, of these receptors and subsequent activation of the downstream signaling molecules Akt, PI3K, and Rap1. The activation of PI3K/Akt results in phosphorylation of the cytoplasmic tail of the β3 integrin, promoting propagation and amplification of "outside-in" signaling, leading to clot retraction, shape change, and subsequent platelet plug stabilization.

Figure 1. Schematic representation of the GAS6/TAM signaling pathway. (Law L A, et al., 2018)

GAS6 and Cancer

The associations of GAS6 with cancer have been reported in a number of cancers. Specifically, GAS6 is overexpressed in glioma, melanoma, schwannoma, and pancreatic ductal adenocarcinoma (PDA) cell lines, and several studies have shown that GAS6 is upregulated in thyroid cancer and ovarian cancer specimens from patients. The functions of TAM receptors in cancers have also been examined in many studies. GAS6 binds to Axl and induces cell survival, proliferation and migration, and overexpression of Axl promotes the development of various cancers. Studies have shown that Axl is upregulated in non-small-cell lung cancer (NSCLC), acute myelocytic leukaemia (AML), melanoma, schwannoma, glioma, osteosarcoma, and thyroid cancer cell lines and that Axl is overexpressed in tumor tissues from patients with NSCLC, AML, osteosarcoma, and thyroid cancer.

GAS6/TAM has an important role in the development of various types of cancers, highlighting GAS6/TAM as attractive targets for therapeutic strategy. Numerous researches considering shRNA knockdown of TAM receptors have been shown effective in inhibition of different kinds of tumors including NSCLC, breast carcinoma, melanoma, osteosarcoma, AML, and thyroid cancer. Besides, selective small-molecule inhibitors of Axl and Mer have been generated. Interestingly, although there is no existing research on GAS6-specific inhibitors, a recent study has developed a novel way to inhibit GAS6/Axl signaling, which may inspire the development of better cancer therapies. The authors designed an Axl 'decoy receptor' that binds GAS6 with a high affinity to inhibit its function, enabling effective sequestration of GAS6 and specific abrogation of Axl signaling. Furthermore, the increased GAS6-binding affinity is crucial and correlates with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo. These results may contribute to future experimental design and increase the potential use of GAS6 as therapeutic targets for cancer.

GAS6 Gene Editing Service

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control GAS6 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

Service	Details	Alternative cell lines or animal species
GAS6 Gene Editing Cell Line Generation	gRNA design and synthesis Transfect the cell lines you're interested Select the high expression cells and sort monoclonal cell Validate the knockout/knockin/point mutation of GAS6 by PCR and sequencing Provide cryogenic preserved vials of stable cells and final reports	HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
GAS6 Gene Editing Animal Model Generation	GAS6 gene conventional knockout animals GAS6 gene conditional knockout animals GAS6 point mutation animals GAS6 knockin animals	Mouse, rat, rabbit, zebrafish, C. elegans, etc.

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