Phosphoinositide-3 kinase binds to a proline-rich motif in the Na~+,K~+-ATPase α subunit and regulates its trafficking

摘要

Endocytosis of Na~+,K~+-ATPase molecules in response to G protein- coupled receptor stimulation requires activation of class I_A phos- phoinositide-3 kinase (PI3K-I_A) in a protein kinase C1dependent manner. In this paper, we report that PI3K-I_A, through its p85_α subunit-SH3 domain, binds to a proline-rich region in the Na~+.K~+- ATPase catalytic α subunit. This interaction is enhanced by protein kinase C-dependent phosphorylation of a serine residue that flanks' the proline-rich motif in the Na~+,K~+-ATPase α subunit and results in increased PI3K-I_A activity, an effect necessary for adaptor protein 2 binding and clathrin recruitment. Thus, Ser-phosphorylation of the Na~+,K~+-ATPase catalytic subunit serves as an anchor signal for regulating the location of PI3K-I_A and its activation during Na~+,K~+- ATPase endocytosis in response to G protein-coupled receptor signals.