Gas6

What is GAS6 Protein?

GAS6 gene (growth arrest specific 6) is a protein coding gene which situated on the long arm of chromosome 13 at locus 13q34. This gene encodes a gamma-carboxyglutamic acid (Gla)-containing protein thought to be involved in the stimulation of cell proliferation. This gene is frequently overexpressed in many cancers and has been implicated as an adverse prognostic marker. Elevated protein levels are additionally associated with a variety of disease states, including venous thromboembolic disease, systemic lupus erythematosus, chronic renal failure, and preeclampsia. The GAS6 protein is consisted of 678 amino acids and GAS6 molecular weight is approximately 74.9 kDa.

What is the Function of GAS6 Protein?

GAS6 protein is a vitamin K-dependent cytokine that binds to members of the TAM family of receptor tyrosine kinases, including Tyro3, Axl, and Mer, and is involved in regulating cell growth, survival, adhesion, and migration. GAS6/Axl signaling plays a role in a variety of biological processes, such as the survival of endothelial cells under acidification conditions, cytokine signaling during natural killer cell development, liver regeneration, survival and migration of gonadotropin-releasing hormone neurons, platelet activation, and regulation of thrombotic response. GAS6 protein expression has been shown to decrease in some cancers, and GAS6 protein may also play an important role in the tumor microenvironment.

Fig1. Role of gas6 in atherosclerosis pathogenesis. (Sandrine Laurance, 2012)

GAS6 Related Signaling Pathway

GAS6 protein, as a key regulator of various biological processes, is involved in several signaling pathways, including Ras-ERK/MAPK, PI3K-Akt, JAK-STAT, etc. It activates these pathways by binding to members of the TAM family of receptor tyrosine kinases (Axl, Tyro3, and MerTK), thereby promoting cell survival, proliferation, migration, and angiogenesis. The GAS6/Axl signaling axis is particularly important in tumor cell invasiveness, metastasis, treatment resistance, and immune escape, and also plays a regulatory role in non-neoplastic diseases such as inflammation and vascular disease. In addition, GAS6 is involved in cell response to apoptotic signals, playing a role in cell fate determination through its anti-apoptotic properties.

GAS6 Related Diseases

GAS6 protein is associated with a variety of diseases, especially in the pathological processes of angiogenesis, inflammation, apoptosis and tumor development. For example, GAS6 plays a key role in promoting tumor cell survival and invasion, regulating platelet function and thrombosis, and participating in immune cell signaling, and its abnormal expression or dysfunction is associated with the development of breast cancer, ovarian cancer, hepatocellular carcinoma, lung cancer and other cancers. It may also be associated with non-neoplastic diseases such as vascular diseases, systemic lupus erythematosus, chronic kidney disease, and preeclampsia.

Bioapplications of GAS6

GAS6 protein has emerged as a potential target for cancer therapy and inflammatory disease intervention due to its key role in cell survival, migration, angiogenesis, and immune regulation. In the field of cancer therapy, small molecule inhibitors, monoclonal antibodies or RNA interference techniques targeting GAS6 or its receptor Axl are being developed to block GAS6-mediated signaling pathways and inhibit tumor cell proliferation and metastasis. In addition, the expression level of GAS6 is also being studied as a biomarker for certain cancers for early diagnosis and prognosis assessment of the disease. In inflammatory diseases, the regulatory role of GAS6 may help control inflammatory processes and provide new ideas for the development of new anti-inflammatory treatment strategies. As a result, GAS6 has a wide range of applications, including drug development, biomarker discovery, and innovation in disease treatment strategies.

Case Study 1: Zihao Yao, 2023

The present study found that synovial macrophages infiltrated and polarized in the obesity microenvironment and identified the essential role of M1 macrophages in impaired macrophage efferocytosis using pathology analysis of obesity-associated OA. Obese OA mice had a more severe cartilage destruction and increased levels of synovial apoptotic cells (ACs) than OA mice in the control group. Enhanced M1-polarized macrophages in obese synovium decreased growth arrest-specific 6 (GAS6) secretion, resulting in impaired macrophage efferocytosis in synovial ACs. Intracellular contents released by accumulated ACs further triggered an immune response and lead to a release of inflammatory factors, such as TNF-α, IL-1β, and IL-6, which induce chondrocyte homeostasis dysfunction in obese OA patients. Intra-articular injection of GAS6 restored the phagocytic capacity of macrophages, reduced the accumulation of local ACs, and decreased the levels of TUNEL and Caspase-3 positive cells, preserving cartilage thickness and preventing the progression of obesity-associated OA.

Fig1. Safranin O staining of human tibial plateaus cartilage explants treated with rhGAS6.

Fig2. Immunoblotting of MMP13, COL2, and senescence markers (p16, p21) in primary chondrocytes treated with rhGAS6.

Case Study 2: Jiawei Fan, 2023

The receptor tyrosine kinases TAM family are highly expressed in multiple forms of cancer cells and tumor-associated macrophages and promote the development of cancers including pancreatic tumor. Targeting TAM receptors could be a promising therapeutic option. Thus in this study, researchers designed a novel CAR based on the extracellular domain of growth arrest-specific protein 6 (GAS6), a natural ligand for all TAM members. The ability of CAR-T to kill pancreatic cancer cells is tested in vitro and in vivo, and the safety is evaluated in mice and nonhuman primate. The results showed that GAS6-CAR-T cells efficiently kill TAM-positive pancreatic cancer cell lines, gemcitabine-resistant cancer cells, and cancer stem-like cells in vitro. GAS6-CAR-T cells also significantly suppressed the growth of PANC1 xenografts and patient-derived xenografts in mice.

Fig3. Cytotoxicity of GAS6-CAR-T cells on TAM-overexpressing HEK-293 T cells.

Fig4. The cytotoxicity of GAS6-CAR-T cells on TAM-low ASPC1 cell lines was tested at varying effector-to-target (E/T) ratios for 24 h.

Gas6 has several biochemical functions, for example, binding, bridging,calcium ion binding,cysteine-type endopeptidase inhibitor activity involved in apoptotic process. Some of the functions are cooperated with other proteins, some of the functions could acted by Gas6 itself. We selected most functions Gas6 had, and list some proteins which have the same functions with Gas6. You can find most of the proteins on our site.

Gas6 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with Gas6 here. Most of them are supplied by our site. Hope this information will be useful for your research of Gas6.

AXL;ppdK;hemC