Effect of Na/K-ATPase-Mediated Signaling on EGFR Signaling Pathway文献综述

Aim

We have known that epithelial growth factor receptor (EGFR) plays an important role in the Na/K-ATPase(NKA)-Mediated Signaling. Binding of ligand such as ouabain or cardiotonic steroids (CTS) actives NKA/Src receptor complex, resulting in the formation a signalosome which phosphorylates EGFR that phosphorylates and assembles other proteins into different signaling modules. This in turn actives downstream signaling pathways eventually resulting in changes in the expression of a series of genes. However, EGFR has also its own signaling pathway. Here, we will test whether Na/K ATPase-Mediated Signaling has an influence on EGFR signaling pathway. The outcome will illustrate a novel molecular mechanism of signal pathway.

Mutations that lead to EGFR overexpression have been associated with a number of cancers[1]. Somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division[2]. In view of a critical role of EGFR in cell growth, it would be of great importance to further dissect alpha;1 NKA-mediated regulation of EGFR and its potential role in cancer biology.

Introduction

1.NKA

NKA was first discovered by Skou in 1957 as the molecular machine for pumping ions across cell membrane[3]. Since then, the structure, the pumping function, and the regulation of the enzyme have been well characterized. NKA, as a large and highly expressed membrane protein complex(most cells contain over one million surface pumps per cell), consists of two noncovalently linked subunits，alpha; and beta;[4][5].The alpha; subunit contains ATP and other ligand binding sites, and is considered as the catalytic subunits. The scaffolding function of beta;subunit is essential for the membrane targeting and full function of the NKA. Four isoforms of NKA have been identified and different isoforms are expressed in a tissue-specific manner. The alpha;1 isoform is found in all cells and is prevalent in all epithelial cells. The alpha;2 and alpha;3 isoform are expressed in skeletal muscle, neuronal tissue, and cardiac myocytes[6][7]. The sequence identity is about 87% among alpha;1, alpha;2 and alpha;3, while alpha;1and alpha;4 are 78% identical. Nevertheless, the overall tertiary structure appears to be identical among all isoforms[8]. And alpha;1 isoform is the major signaling isoform whereas the others are not.

NKA is a member of the P-type ATPase family. In addition to pumping ions across cell membrane, it is engaged in non-pumping functions. For example, very low concentration of CTS actives ligands that result in assembly of multiple protein complexes which allow NKA to perform its signal transduction.

2.EGFR

The epidermal growth factor receptor (EGFR) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. EGFR dimerization stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR occurs. These include Y992, Y1045, Y1068, Y1148 and Y1173[9]. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosine through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation[10]. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation.

3. Na/K-ATPase-Mediated Signaling