Ste20-related proline/alanine-rich kinase: a novel regulator of intestinal inflammation

Abstract

Recently, inflammatory bowel disease (IBD) has been the subject of considerable research, with increasing attention being paid to the loss of intestinal epithelial cell barrier function as a mechanism of pathogenesis. Ste20-related proline/alanine-rich kinase (SPAK) is involved in regulating barrier function. SPAK is known to interact with inflammation-related kinases (such as p38, JNK, NKCC1, PKCtheta, WNK and MLCK), and with transcription factor AP-1, resulting in diverse biological phenomena, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and regulation of chloride transport. This review examines the involvement of Ste20-like kinases and downstream mitogen-activated protein kinases (MAPKs) pathways in the pathogenesis and control of intestinal inflammation. The primary focus will be on the molecular features of intestinal inflammation, with an emphasis on the interaction between SPAK and other molecules, and the effect of these interactions on homeostatic maintenance, cell volume regulation and increased cell permeability in intestinal inflammation.

Figure 1

Pathogenesis of IBD. Many different factors, such as genetic factors, environmental factors, and intestinal non-pathogenic or pathogenic bacteria can damage the mucus, epithelium, or the tight junction, to initiate the inappropriate regulation or deregulation of the immune response, leading to the secretion of pro-inflammatory cytokines, decrease in epithelial barrier function and initiation of the inflammation-related signaling pathways. IEC: Intestinal epithelial cell; APC: Antigen presenting cell; TJ: Tight junction.

Figure 2

Ste20 kinases participate in inflammation. Ste20 kinases that function as an MAP4K can activate MAP3K, MAP2K and MAPK, leading to the inflammatory functions. This model adapted from the model presented in http://www.cellsignal.com/pathways/map-kinase.jsp. MAPK: Mitogen-activated protein kinase. GPCR: G-protein coupled receptor; PAK: p21 activated kinase; GCK: Germinal central kinase; MLK: Multiple lineage kinase; TAK: Tat-associated kinase; DLK: Dual leucine zipper-bearing kinase; MEK: MAPK/Erk kinase; MEKK: MEK kinase; ASK: Aspartate kinase; MKK: MAPK kinase; Erk: Extracellular signal-regulated kinase; SAPK: Stress-activated protein kinase; JNK: Jun-amino-terminal kinase.

Figure 3

SPAK interacts with other molecules to maintain cellular homeostasis. SPAK can be a substrate, indirectly or directly, for pro-inflammatory cytokines, environmental stress including hypertonicity, some other kinases such as PKCtheta;, WNK1/4, or other receptors, for example TRAIL & RELT. Also SPAK can function as upstream kinase to JNK, p38, or ion transport NKCC1/KCC, transcription factor AP-1, as well as MLCK. WNK: With no lysine kinase 1/4; TRIL: TNF-related apoptosis-inducing ligand; RELT: Receptor expressed in lymphoid tissues; MLCK: Myosin II regulatory light chain kinase; NKCC1: Sodium potassium chloride chloride transporter 1; KCC: Potassium chloride chloride transporter; AP-1: Activating protein 1.