The product of a gas6 splice variant allows the release of the domain responsible for Axl tyrosine kinase receptor activation.
The product of gas6 (Gas6) is a growth factor with high level of similarity to protein S and was identified as the ligand for Axl family of tyrosine kinase receptors. Gas6 contains an N-terminal gamma-carboxylated domain (Gla), four epidermal growth factor like domains and a large C-terminal D region. An alternative Gas6 spliced form (Gas6SV) having an additional 43 amino acids between fourth EFG like and D domain was characterised. Here we show data indicating that Gas6SV is specifically cleaved within the inserted sequence, thereby splitting the D domain from the remaining part of the protein. The resulting two proteolytic products of 36 kDa and 50 kDa were separated and the 50 kDa fragment corresponding to region D was shown to be responsible for Axl receptor activation. Furthermore a deletion mutant of Gas6 containing only the D domain was shown to similarly activate Axl receptor phosphorylation unequivocally demonstrating that D domain can act as a signalling molecule. The possible roles of the proteolytic processing of Gas6SV in the regulation of growth factor availability are discussed.
Goruppi
S
S
L.N.C.I.B. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, AREA Science Park, Padriciano, Trieste, Italy.
Yamane
H
H
Marcandalli
P
P
Garcia
A
A
Clogston
C
C
Gostissa
M
M
Varnum
B
B
Schneider
C
C
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D014162:Transfection; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D004815:Epidermal Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human