Calcium-binding protein 39 in with-no-lysine kinase signaling and the modulation of renal tubular transport.

Abstract

Purpose of review: The regulation of renal tubular transport is essential for maintaining electrolyte balance and blood pressure. Calcium-binding protein 39 (Cab39), also known as mouse protein-25 (MO25), plays a pivotal role in modulating this process through its interaction with WNK (with no lysine) kinases and Ste20-like kinases, including STE20/SPS1-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). By stabilizing and facilitating the activation of these kinases, Cab39 plays a crucial role in the regulation of key ion transporters, such as the sodium-chloride cotransporter (NCC) and the sodium-potassium-chloride cotransporters (NKCC1 and NKCC2). This review provides a comprehensive analysis of Cab39 structural properties, molecular interactions, and functional roles in renal physiology, emphasizing its significance in ion homeostasis.

Recent findings: Studies reveal that Cab39 enhances SPAK activity up to 100-fold. Importantly, the role of Cab39 extends beyond simple kinase activation, as it supports kinase complex assembly and localization, enabling precise control over transporter regulation. Evidence also suggests that Cab39 may influence the regulation of NCC and NKCC2 through similar mechanisms, making it a promising target for therapeutic interventions in disorders such as hypertension and salt-wasting syndromes.

Summary: The discovery of a small-molecule Cab39 inhibitor highlights its potential as a pharmacological target. Understanding the multifaceted functions of Cab39 may unlock novel strategies for managing renal and cardiovascular disorders.