Receptor-mediated Golgi retention of Fam20 kinases tunes secretome phosphorylation during lactation

Fam20C, the first protein kinase identified in the secretory pathway, governs the majority phosphorylation of the secretome. Although Fam20C has a high propensity for secretion, its kinase activity occurs intracellularly. How Fam20C clients are phosphorylated inside cells remains elusive. Here, we demonstrate that the pseudokinase Fam20A forms a heterocomplex with Fam20C on the Golgi membrane, anchoring the cleaved, mature form of Fam20C within the Golgi. Their Golgi localization is promoted by a set of cargo receptors ERGIC2 and ERGIC3, which drive the ER-to-Golgi transport of Fam20A-Fam20C. Importantly, both ERGIC2 and ERGIC3 are upregulated in the mammary gland during lactation, and Ergic2 or Ergic3 knockout mice display global changes in secretome phosphorylation, less phosphorylated β-casein in milk, and deficiency in offspring growth. Our findings uncover a previously unrecognized mechanism for the spatiotemporal regulation of Fam20 kinases, crucial for efficient phosphorylation of secretory proteins during lactation.