Sci. STKE, 12 August 2003
POLARITY An Escort to the Top
ErbB2, a receptor tyrosine kinase that is the preferred association partner of other proteins in the ErbB (or epidermal growth factor receptor) family, enhances ligand binding and signaling from its partners but does not itself bind soluble ligand. The heterodimeric glycoprotein sialomucin complex (SMC, also known as Muc4) appears to act as an intramembrane ligand that binds and activates ErbB2, thereby potentiating ErbB2-ErbB3 heterodimer signaling. In polarized epithelial cells, SMC is localized in the apical membrane, whereas ErbB receptors are generally believed to localize to the basolateral membrane (which allows access to bloodborne ligands). Ramsauer et al. showed that this was not always the case. The authors used confocal microscopy together with immunofluorescence analysis to determine whether ErbB2 and SMC associated with each other in polar epithelia. In CACO-2 epithelial cells, which did not have detectable basal levels of SMC, ErbB3 was associated with junctions at the lateral cell surface. In CACO-2 cells transiently transfected with SMC, however, ErbB2 associated with SMC and translocated to the apical surface. SMC transfection also stimulated ErbB2 phosphorylation. ErbB2 was associated with membrane SMC (but not a soluble form of SMC) in various epithelia that express SMC, generally on the apical surface. Thus, SMC appears to alter ErbB2 localization, as well as to modulate its signaling. The authors suggest that apical localization of ErbB2 may provide a sensor of epithelial integrity. In this model, loss of polarity would lead to basolateral localization of ErbB2 and exposure to basolateral components, thereby activating additional signaling pathways and flipping a "proliferation" switch; SMC, by regulating ErbB2 localization, would modulate the activity of such a switch.
V. P. Ramsauer, C. A. Carothers Carraway, P. J. I. Salas, K. L. Carraway, Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized epithelial cells. J. Biol. Chem. 278, 30142-30147 (2003). [Abstract] [Full Text]
Citation: An Escort to the Top. Sci. STKE 2003, tw313 (2003).
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