Autosomal Recessive Polycystic Kidney Disease Epithelial Cell Model Reveals Multiple Basolateral Epidermal Growth Factor Receptor Sorting Pathways

Abstract

We have discovered that multiple basolateral pathways mediate EGF receptor sorting in renal epithelial cells. The polycystic kidney disease allele in the BPK mouse model, Bicc1, interferes with one specific EGF receptor pathway, causing nonpolar delivery of the receptor without affecting overall cell polarity.

Growth Factor Identity Is Encoded by Discrete Coiled-Coil Rotamers in the EGFR Juxtamembrane Region

“…First, it is possible that proteins known to bind to the JM-A region and induce various signaling pathways, such as calmodulin (Martin-Nieto and Villalobo, 1998), Nck adaptor protein (Hake et al, 2008), Gα S (Poppleton et al, 2000), PKC (Hunter et al, 1984), p38 MAPK (Takishima et al, 1988), are preferentially recruited by one specific JM conformation. It is also possible that differential display of nuclear (Lin et al, 2001) and basolateral (Ryan et al, 2010) sorting motifs in the JM-A could differentially traffic the receptor. Lastly, specific JM-A conformations could directly bind to the surface of the asymmetric kinase dimer leading to further propagation of subtle conformational changes through the kinase domains and differential C-terminal tail phosphorylation (Wilson et al, 2009).…”

Trafficking of Epidermal Growth Factor Receptor Ligands in Polarized Epithelial Cells

“…The basolateral sorting of EGFR has been characterized in detail; it is mediated by a bipartite motif in the juxtamembrane region, which is composed of a dileucine motif proximal to a PXXP motif (Figure 7) (96, 97, 125). Additionally, basolateral sorting is also controlled by posttranslational phosphorylation within this region (126). These components display a sorting hierarchy, indicating that EGFR may switch between various sorting pathways in a context-dependent manner (126, 127).…”

“…Additionally, basolateral sorting is also controlled by posttranslational phosphorylation within this region (126). These components display a sorting hierarchy, indicating that EGFR may switch between various sorting pathways in a context-dependent manner (126, 127). A similar basolateral sorting motif has been described for ERBB2 (128).…”

From wavy hair to naked proteins: The role of transforming growth factor alpha in health and disease

“…Moreover, NKD2 loss would also induce signaling aberrations in canonical Wnt signaling pathways in addition to dysregulation of EGFR signaling. On a related note, EGFR mistrafficking itself has been observed and correlates with pathological conditions, such as autosomal recessive polycystic kidney disease, where EGFR mislocalizes to apical membranes [108]. EGFR mutants engineered to mistraffick to the apical surface also show aberrant cyst morphology that often correlates with transformation in vivo [109].…”