Roles of γ‐carboxylation and a sex hormone‐binding globulin‐like domain in receptor‐binding and in biological activities of Gas6

Abstract

Gas6 is a ligand for an Axl/Sky receptor tyrosine kinase subfamily and has a structure composed of a Gla domain, four EGF-like domains and a C-terminal sex hormone-binding globulin (SHBG)-like domain. When examining the role of each domain in receptor-binding and biological activities of Gas6, we found that receptor-binding and mitogenic activities were markedly reduced by inhibiting γ-carboxylation of the Gla domain, while a Gas6 mutant composed of only an SHBG-like domain retained both of these activities. Thus, the SHBG-like domain is apparently an entity indispensable for Gas6 activities, and γ-carboxylation of the Gla domain has a regulatory role in retaining the activity of native Gas6.

Biology of the TAM Receptors

“…1). 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).…”

TAM Receptor Signalling and Demyelination

“…Numerous studies have shown that the LG domains mediate binding to the TAM receptors [9,25,26] . In particular, examination of the crystal structure of the Gas6/ Axl complex revealed that the functional signalling complex is a heterotetramer formed from 2 receptor molecules and 2 ligand molecules in a circular structure [9] .…”

Gas6 Binding to Photoreceptor Outer Segments Requires γ-Carboxyglutamic Acid (Gla) and Ca2+ and is Required for OS Phagocytosis by RPE Cells in vitro

“…Members of this family are distinguished by regions rich in negatively charged g-carboxyglutamic acid (Gla), which promote Ca 2 -dependent binding to membrane phosphatidylserine (PS) (Tanabe et al, 1997;Nakano et al, 1997a). In Gas6, the Gla domain and the receptor (e.g.…”