The first laminin G-type domain in the SHBG-like region of protein S contains residues essential for activation of the receptor tyrosine kinase sky.
Vitamin K-dependent protein S and the product of growth-arrest-specific gene 6 (Gas6) both possess the ability to phosphorylate members of the Axl/Sky subfamily of receptor tyrosine kinases. However, Gas6 appears to be the bona fide ligand for these receptors in man, as human protein S has been demonstrated to activate murine Sky but not the human orthologue. In contrast, bovine protein S is able to stimulate human Sky despite its high degree of sequence identity with human protein S. The domain organisations of protein S and Gas6 are virtually identical and the C-terminal SHBG-like region, containing two globular (G) domains, has been shown to play a crucial role in the receptor stimulation. In order to further localise the area responsible for the interaction, a number of protein chimeras were used to stimulate human Sky. Each chimera had one part of the human protein S SHBG-like region replaced by the corresponding part of bovine protein S or human Gas6. We found that human protein S may indeed activate human Sky but only above physiological plasma concentrations. The human-bovine protein S chimeras provided new information implying that the first G domain contains critical residues for the interaction with the Sky receptor. Moreover, these residues do not seem to be clustered but rather to be distributed at various positions in the first G domain.
Evenäs
P
P
Department of Clinical Chemistry, Lund University, University Hospital, Malmö, Sweden.
Dahlbäck
B
B
García de Frutos
P
P
D000818:Animals; D002417:Cattle; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin / Q000737:chemistry*; D008297:Male; D010766:Phosphorylation; D017293:Protein S / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D017293:Protein S; D011506:Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014443:Tyrosine; D000099255:Growth Arrest-Specific Protein 6; C084944:TYRO3 protein, human