Regulation of ABC Transporter Function Via Phosphorylation by Protein Kinases

Abstract

ATP-binding cassette (ABC) transporters are multispanning membrane proteins that utilize ATP to move a broad range of substrates across cellular membranes. ABC transporters are involved in a number of human disorders and diseases [1]. Overexpression of a subset of the transporters has been closely linked to multidrug resistance in both bacteria and viruses and in cancer. A poorly understood and important aspect of ABC transporter biology is the role of phosphorylation as a mechanism to regulate transporter function. In this review, we summarize the current literature addressing the role of phosphorylation in regulating ABC transporter function. A comprehensive list of all the phosphorylation sites that have been identified for the human ABC transporters is presented, and we discuss the role of individual kinases in regulating transporter function. We address the potential pitfalls and difficulties associated with identifying phosphorylation sites and the corresponding kinase(s), and we discuss novel techniques that may circumvent these problems. We conclude by providing a brief perspective on studying ABC transporter phosphorylation.

A High-Resolution Tissue-Specific Proteome and Phosphoproteome Atlas of Maize Primary Roots Reveals Functional Gradients along the Root Axes

“…ABC transporters, at least in humans, are regulated by phosphorylation via protein kinases, which was recently reviewed (Stolarczyk et al, 2011). Among the stele-specific phosphoproteins, GO terms related to protein kinases were also enriched (Supplemental Table S1), which could be in line with the high ABC transporter activity and its activation by kinase-dependent phosphorylation in this tissue (Stolarczyk et al, 2011).…”

“…ABC transporters are transmembrane proteins enabling the transport of hormones, lipids, metals, and other molecules (for review, see Higgins, 1992) via ATP hydrolysis at the ABC, representing a nucleotidebinding domain (Higgins and Linton, 2004). ABC transporters, at least in humans, are regulated by phosphorylation via protein kinases, which was recently reviewed (Stolarczyk et al, 2011). Among the stele-specific phosphoproteins, GO terms related to protein kinases were also enriched (Supplemental Table S1), which could be in line with the high ABC transporter activity and its activation by kinase-dependent phosphorylation in this tissue (Stolarczyk et al, 2011).…”

Phosphorylation-dependent Changes in Nucleotide Binding, Conformation, and Dynamics of the First Nucleotide Binding Domain (NBD1) of the Sulfonylurea Receptor 2B (SUR2B)

“…ABC transporters are phosphorylated at specific sites in the NBDs and/or in the NBD1-MSD2 linker by various kinases, with the effects of phosphorylation depending on the specific site phosphorylated (81). For example, phosphorylation of ABCA1 at NBD2 is required for full cholesterol transport activity, whereas phosphorylation of the NBD1-MSD2 linker affects protein stability (81)(82)(83).…”

“…ABC transporters are phosphorylated at specific sites in the NBDs and/or in the NBD1-MSD2 linker by various kinases, with the effects of phosphorylation depending on the specific site phosphorylated (81). For example, phosphorylation of ABCA1 at NBD2 is required for full cholesterol transport activity, whereas phosphorylation of the NBD1-MSD2 linker affects protein stability (81)(82)(83). ABCB1, which is also known as P-glycoprotein and is associated with multidrug resistance in cancers (84), is also phosphorylated at a number of sites in the NBD1-MSD2 linker by PKA, protein kinase C, and casein kinase 2 (81).…”

“…For example, phosphorylation of ABCA1 at NBD2 is required for full cholesterol transport activity, whereas phosphorylation of the NBD1-MSD2 linker affects protein stability (81)(82)(83). ABCB1, which is also known as P-glycoprotein and is associated with multidrug resistance in cancers (84), is also phosphorylated at a number of sites in the NBD1-MSD2 linker by PKA, protein kinase C, and casein kinase 2 (81). PKC phosphorylation increases the ATPase activity of ABCB1 and regulates efflux of anions.…”