Nephronectin: An Extracellular Matrix Protein with Diverse <em></em> Functions

Review Article

J Dent & Oral Disord. 2016; 2(1): 1004.

Nephronectin: An Extracellular Matrix Protein with Diverse Functions

Yamada A* and Kamijo R

Department of Biochemistry, School of Dentistry, Showa University, Japan

*Corresponding author: Yamada A, Department of Biochemistry, School of Dentistry, Showa University, Shinagawa, Tokyo, Japan

Received: December 25, 2015; Accepted: January 18, 2016; Published: January 20, 2016


Nephronectin, an extracellular matrix protein also known as POEM, is considered to play critical roles in the development and functions of various tissues. This protein is associated with integrins, especially integrin a8β1, which are extracellular matrix receptors, through its own RGD motif, while interactions between nephronectin and integrin a8β1 are essential for early kidney development. The gene expression of nephronectin is regulated by various cytokines in osteoblasts, and enhances osteoblast differentiation and mineralization via EGF repeats and the 3’ UTR of its mRNA suggesting the important role of nephronectin in development and metabolism of bone. Nephronectin also plays important roles in vascularization of cardiac tissue, as well as the limbal and hair follicle stem cell niche. This review summarizes the rapidly evolving understanding of nephronectin, including protein and gene organization, expression and regulation, and effects both in vitro and . Recent novel findings have led to a new paradigm for matrix biology with major novel implications in regard to tissue development and morphogenesis.

Keywords: Nephronectin; Extracellular matrix protein; Kidney development; Osteoblast differentiation


PCR: Polymerase Chain Reaction; EGF: Epidermal Growth Factor; ECM: Extra-Cellular Matrix; POEM: Pre-Osteoblast Epidermal Growth Factor-Like Repeat Protein with Meprin, A5 Protein, and Receptor Protein-Tyrosine Phosphatase μdomain; MAM: Meprin, A5 Protein, And Receptor Protein-Tyrosine Phosphatase μ; AP, ALP: Alkaline Phosphatase; ORF: Open Reading Frame; RGD: Arg-Gly- Asp; GDNF: Glia Cell-Line Derived Neurotrophic Factor; TGF-β: Transforming Growth Factor-β; TNF-a: Tumor Necrosis Factor-a; OSM: Oncostatin M; ERK: Extracellular Signal-Regulated Kinase; JNK: C-Jun N-Terminal Kinase; MAPK: Mitogen Activated Protein Kinase; NF-κB: Nuclear Factor Kappa B; UTR: Untranslated Region


Extracellular matrix proteins are involved in a variety of biological functions, including cell growth, cell differentiation, and apoptosis. Recent findings have shown that in addition to the ability of extracellular molecules to communicate and interact with cells, specific interactions between extracellular molecules are essential for correct matrix organization and function [1]. Nephronectin, an extracellular matrix protein, was independently identified by two different groups at nearly the same time. Morimura et al. generated a pair of degenerate PCR primers based on EGF-like repeat structures found in various ECM and receptor proteins using single-strand cDNA from an osteoblast cell line (MC3T3-E1) as a template in order to isolate novel EGF-like repeats containing such genes as fibrillin and laminin [2]. Based on their results, a novel molecule termed preosteoblast Epidermal Growth Factor (EGF)-like repeat protein with meprin, A5 protein, and receptor Protein-Tyrosine Phosphatase μ domain (POEM) was reported. On the other hand, Brandenberger et al. sought to identify a ligand that mediates integrin a8β1 function during kidney morphogenesis in order to understand the mechanisms of integrin a8β1 function. They used soluble integrin a8β1-Alkaline Phosphatase (AP), which consisted of a heterodimer of the extra cellular domains of a8 and β1 fused to AP, in order to identify novel integrin a8β1-binding proteins in embryonic kidney extracts [3].

Nephronectin Protein Structures

Figure 1 shows the deduced nephronectin protein structure. A putative signal peptide representing the expected amino acid sequence is located at the NH2 terminus of the ORF of nephronectin, while no other hydrophobic regions serving as a transmembrane domain were found, suggesting that nephronectin is a secreted protein [4]. Nephronectin also contains five EGF-like repeats, a proline rich domain, and a region at the COOH terminus that shares homology with MAM repeats. It belongs to a group of small type EGF-repeat proteins that includes MAEG, Pref-1, EGFL6, Del1, DANCE, S1-5, DBI, and Spe-9, each of which play important roles in the functions and development of various organs [5-10]. Additionally, nephronectin contains an RGD (Arg-Gly-Asp) cell adhesion sequence motif. Sato et al. demonstrated that the LFEIFEIER (Lue-Phe-Glu- Ile-Phe-Glu-Ile-Glu-Arg) sequence on the COOH terminus of its RGD motif serves as a synergy site to ensure specific high-affinity binding of nephronectin to integrin a8 and β1 [11]. Nephronectin strongly binds to heparin, but not to Chondroitin Sulfate (CS)-E and moderately to heparan sulfate, while it fails to bind to CS-A, CS-C, CS-D, dermatan sulfate, and hyaluronic acid via its MAM domain [12]. Furthermore, Sanchez-Cortes et al. demonstrated that the FEI (Phe-Glu-Ile) motif in nephronectin can independently mediate cell adhesion of the RGD site, and both the RGD and FEI sequences in nephronectin synergistically bind to integrin a8β1 [13].