Trafficking of Epidermal Growth Factor Receptor Ligands in Polarized Epithelial Cells

Abstract

A largely unilamellar epithelial layer lines body cavities and organ ducts such as the digestive tract and kidney tubules. This polarized epithelium is composed of biochemically and functionally separate apical and basolateral surfaces. The epidermal growth factor receptor (EGFR) signaling pathway is a critical regulator of epithelial homeostasis and is perturbed in a number of epithelial disorders. It is underappreciated that in vivo EGFR signaling is most often initiated by cell-surface delivery and processing of one of seven transmembrane ligands, resulting in release of the soluble form that binds EGFR. In polarized epithelial cells, EGFR is restricted largely to the basolateral surface, and apical or basolateral ligand delivery therefore has important biological consequences. In vitro approaches have been used to study the biosynthesis, cell-surface delivery, proteolytic processing, and release of soluble EGFR ligands in polarized epithelial cells. We review these results, discuss their relevance to normal physiology, and demonstrate the pathophysiological consequences of aberrant trafficking. These studies have uncovered a rich diversity of apico-basolateral trafficking mechanisms among the EGFR ligands, provided insights into the pathogenesis of an inherited magnesium-wasting disorder of the kidney (isolated renal hypomagnesemia), and identified a new mode of EGFR ligand signaling via exosomes.

Induction of lateral lumens by disruption of a monoleucine-based basolateral sorting motif in betacellulin

“…This study further underscores the cell biology that has been uncovered by studying the trafficking of each of the EGFR ligands in polarized epithelial cells (Singh and Coffey, 2014b). For example, basolateral delivery of TGFA depends on the Wnt negative regulator NKD2, providing a point of convergence between EGFR-related events and Wnt signaling (Li et al, 2004).…”

“…Interestingly, this motif is also present in HBEGF, another basolateral EGFR ligand, and we speculate that this motif might direct basolateral sorting of HBEGF (supplementary material Fig. S1B) (Nakamura et al, 1995;Singh and Coffey, 2014b). Thus, the EExxxL basolateral-sorting motif is the most common basolateral-sorting motif amongst the family of mammalian EGFR ligands; a PxxP motif in EGF, a dileucine motif in TGFA and a YxxΦ motif in EREG are represented only once (Dempsey et al, 2003;Gephart et al, 2011;Groenestege et al, 2007;Singh et al, 2013).…”

“…A human cancer-associated mutation (E156K) disrupts the BTC basolateral-sorting motif and specificity Seventeen different mutations in the coding region of BTC have been reported in human cancers in the cBio cancer genomics portal (www.cbioportal.org) (Cerami et al, 2012;Singh and Coffey, 2014b). Two of these mutations (G101stop in lung adenocarcinoma and E156K in melanoma) are predicted to remove or disrupt the basolateral-sorting motif.…”

“…Of the seven EGFR ligands, BTC, along with EREG and HBEGF, also bind to another EGFR family member, ERBB4. However, of these, only BTC and HBEGF contain the EExxxL trafficking motif (Singh and Coffey, 2014b). HBEGF in turn does not contain the juxtamembrane cytosolic cysteine residues and has not been shown to undergo regulated intramembranous proteolysis, unlike BTC (Stoeck et al, 2010).…”

“…All of these ligands are synthesized as type 1 transmembrane precursors. Proteolytic cleavage within the ectodomain releases the mature soluble ligand that binds to the receptor and initiates a complex cascade of downstream signaling events (Singh and Coffey, 2014b).…”