Polar expression of ErbB-2/HER2 in epithelia. Bimodal regulation by Lin-7.
ErbB-2/HER2 drives epithelial malignancies by forming heterodimers with growth factor receptors. The primordial invertebrate receptor is sorted to the basolateral epithelial surface by binding of the PDZ domain of Lin-7 to the receptor's tail. We show that all four human ErbBs are basolaterally expressed, even when the tail motif is absent. Mutagenesis of hLin-7 unveiled a second domain, KID, that binds to the kinase region of ErbBs. The PDZ interaction mediates stabilization of ErbB-2 at the basolateral surface. On the other hand, binding of KID is involved in initial delivery to the basolateral surface, and in its absence, unprocessed ErbB-2 molecules are diverted to the apical surface. Hence, distinct domains of Lin-7 regulate receptor delivery to and maintenance at the basolateral surface of epithelia.
Shelly
Maya
M
Department of Biological Regulation, The Weizmann Institute of Science, 76100, Rehovot, Israel.
Mosesson
Yaron
Y
Citri
Ami
A
Lavi
Sara
S
Zwang
Yaara
Y
Melamed-Book
Naomi
N
Aroeti
Benjamin
B
Yarden
Yosef
Y
D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D002460:Cell Line; D016764:Cell Polarity; D004285:Dogs; D004848:Epithelium / Q000378:metabolism*; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins / Q000502:physiology*; D009154:Mutation; D021381:Protein Transport / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C099173:LIN-7 protein, C elegans