Gas6-mediated signaling is dependent on the engagement of its gamma-carboxyglutamic acid domain with phosphatidylserine

Rajotte, Isabelle; Hasanbasic, Ines; Blostein, Mark

doi:10.1016/j.bbrc.2008.08.083

Cited by 25 publications

(21 citation statements)

References 26 publications

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“…Both Gas6 and Protein S consist of an N-terminal domain rich in γ-carboxyglutamic acid residues (Gla) that binds to PtdSer ( Fig. 1) (Huang et al, 2003;Ishimoto et al, 2000;Rajotte et al, 2008), a loop region, four epidermal growth factor-like repeats, and two C-terminal laminin G-like domains forming a sex hormone-binding globulin-like structure that binds to the Ig-like domains of the TAM receptors (Sasaki et al, 2006(Sasaki et al, , 2002. Dimerization of TAM receptors occurs after binding of their ligands, resulting in a 2:2 complex, and is necessary for signaling (Sasaki et al, 2006).…”

Section: Protein S and Gas6/tyro3 Axl And Mermentioning

confidence: 99%

Phosphatidylserine receptors: Enhancers of enveloped virus entry and infection

2014

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A variety of both RNA and DNA viruses envelop their capsids in a lipid bilayer. One of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (PtdSer). Surface exposure of PtdSer disguises viruses as apoptotic bodies; tricking cells into engulfing virions. This mechanism is termed apoptotic mimicry. Several PtdSer receptors have been identified to enhance virus entry and we have termed this group of proteins PtdSer-mediated virus entry enhancing receptors or PVEERs. These receptors enhance entry of a broad range of enveloped viruses. Internalization of virions by PVEERs provides a broad mechanism of entry with little investment by the virus itself and may allow some viruses to attach to cells, thereby making viral glycoprotein/cellular receptor interactions more probable. Alternatively, other viruses may rely entirely on PVEERs for internalization into endosomes. This review provides an overview of PtdSer receptors that serve as PVEERs and the biology behind virion/PVEER interaction.

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Section: Protein S and Gas6/tyro3 Axl And Mermentioning

confidence: 99%

Phosphatidylserine receptors: Enhancers of enveloped virus entry and infection

2014

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“…The TAM ligands Gas6 and protein S both bind PtdSer, and many studies have highlighted the importance of this interaction to activation of TAM receptors, though the exact means by which information is transduced from lipid to receptor via ligand is controversial (Dormady et al, 2000; Hall et al, 2002; Hasanbasic et al, 2005; Rajotte et al, 2008; Stenhoff et al, 2004; Yanagita et al, 1999). Earlier work identified PtdSer as an important factor to TAM activation, although it concluded that interaction between the ligand and receptor was entirely dependent upon lipid interaction, which has proven to not be the case (Nakano et al, 1997; Tanabe et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

The AXL Receptor Is a Sensor of Ligand Spatial Heterogeneity

2015

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The AXL receptor is a TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) important in physiological inflammatory processes such as blood clotting, viral infection, and innate immune-mediated cell clearance. Overexpression of the receptor in a number of solid tumors is increasingly appreciated as a key drug resistance and tumor dissemination mechanism. Although the ligand-receptor (Gas6-AXL) complex structure is known, literature reports on ligand-mediated signaling have provided conflicting conclusions regarding the influence of other factors such as phosphatidylserine binding, and a detailed, mechanistic picture of AXL activation has not emerged. Integrating quantitative experiments with mathematical modeling, we show here that AXL operates to sense local spatial heterogeneity in ligand concentration, a feature consistent with its physiological role in inflammatory cell responses. This effect arises as a result of an intricate reaction-diffusion interaction. Our results demonstrate that AXL functions distinctly from other RTK families, a vital insight for envisioned design of AXL-targeted therapeutic intervention.

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“…This SHBG domain binds to the Ig domains of the receptors and induces their dimerization and subsequent kinase activation (Nyberg et al 1997;Tanabe et al 1997;Evenas et al 2000;Sasaki et al 2002Sasaki et al , 2006. The second is a so-called Gla domain positioned at the very amino terminus of both Gas6 and Pros1 (Stitt et al 1995;Ishimoto et al 2000;Rajotte et al 2008). (The SHBG and Gla domains are separated by four EGF-related domains.)…”

Section: Lg1mentioning

confidence: 99%