Gas6 and Other Vitamin KRequiring Gla Proteins

A Gla protein that is associated with the central nervous system, rather than with liver or bone, was discovered in 1993. In tissue culture models it had the properties of a growth arrest-specific (GAS) cell-signalling gene product. It acts as a ligand for a number of receptor protein kinases; it potentiates the growth of vascular smooth muscle cells, Schwann cells, and the neurons that synthesize gonadotropin-releasing hormones; and it can prevent apoptotic cell death. Knockout mice in which three Gas6 receptors are mutated had major neurological and spermatogenic abnormalities. There is interest in potential roles for Gas6 in Alzheimer's disease and Parkinson's disease. Clearly, these properties and emerging roles have helped to confirm the growing suspicion that vitamin K-dependent Gla proteins possess key functions beyond blood clotting and even bone remodelling. Gas6 has a MW of 75,000 with 11 or 12 Gla residues, and its structure is partly homologous with protein S.

Even less well characterized are several other Gla proteins from a variety of tissues. Kidney contains 'nephrocalcin,' with just two or three Gla residues, which may be involved in renal calcium transport (another important function that may be impaired by vitamin K deficiency in man). Atherocalcin, or plaque Gla protein, may be related or even identical to MGP. Proline-rich Gla proteins PRGP-1 and PRGP-2 are found predominantly in the spinal cord and thyroid gland, respectively, but their functions are unknown. Gla proteins occur in most vertebrates and also in molluscs, so their evolutionary appearance in the animal kingdom is probably quite ancient in origin.

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