Fam198a, a member of secreted kinase, secrets through caveolae biogenesis pathway

Fam198a is a member of four-jointed protein kinases, a secreted protein kinase family. It was identified as a caveolae-associated protein and colocalized with cavin-1 and caveolin-1 in both tissues and cells. The newly synthesized Fam198a precursor in endoplasmic reticulum (ER) was transported by caveolae biogenesis vesicles to Golgi apparatus in which it was proteolytically cleaved into the secreted mature form. The amino acid mutation analysis identified Arg 120 and 437 as the proteolytic sites in Fam198a precursor during maturation. In mouse embryo fibroblasts (MEFs) obtained from cavin-1-/- or caveolin-1-/- mice, Fam198a precursor was retained in ER and no mature Fam198a could be formed in these cells. Ectopic expression of exogenous cavin-1 in cavin-1-/- MEFs restored the blocked Fam198a post-translational process and secretion. Cavin-1 was also required for Fam198a secretion after its maturation in Golgi apparatus. Ectopic expression of cavin-1 in A549 cells restored the blocked Fam198a secretion. These results suggest that protein secretion is an important function for caveolae biogenesis pathway and the disruption of caveolae system will affect those functions played by the secreted proteins.