Muc4/Sialomucin Complex, the Intramembrane ErbB2 Ligand, Translocates ErbB2 to the Apical Surface in Polarized Epithelial Cells

Palau, Victoria; Carraway, Coralie A. Carothers; Salas, Pedro J.; Carraway, Kermit L.

doi:10.1074/jbc.m303220200

Cited by 78 publications

(79 citation statements)

References 26 publications

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“…In contrast, we previously showed that expression of Muc4 in these cells results in a relocation of ErbB2 from the lateral to the apical surface (Ramsauer et al, 2003).…”

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confidence: 92%

“…CACO-2 cells, whether expressing Muc4 or not expressing Muc4, exhibited ErbB3 in a basolateral location ( Figure 4B). In contrast, we previously showed that expression of Muc4 in these cells results in a relocation of ErbB2 from the lateral to the apical surface (Ramsauer et al, 2003).To determine the effect of ErbB3 localization on complex formation between the Muc4 -ErbB2 complex and ErbB3, we immunoprecipitated Muc4 from cell lysates of Muc4-expressing, polarized CACO-2 cells with two different antibodies against Muc4, and analyzed the immunoprecipitates by immunoblotting for ErbB2 and ErbB3. ErbB2, but not In Muc4-expressing cells, ErbB2 is colocalized at the apical surface with Muc4, as we had demonstrated previously (Ramsauer et al, 2003).…”

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confidence: 99%

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Muc4–ErbB2 Complex Formation and Signaling in Polarized CACO-2 Epithelial Cells Indicate That Muc4 Acts as an Unorthodox Ligand for ErbB2

Palau

Pino

Farooq

et al. 2006

MBoC

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Muc4 serves as an intramembrane ligand for the receptor tyrosine kinase ErbB2. The time to complex formation and the stoichiometry of the complex were determined to be <15 min and 1:1 by analyses of Muc4 and ErbB2 coexpressed in insect cells and A375 tumor cells. In polarized CACO-2 cells, Muc4 expression causes relocalization of ErbB2, but not its heterodimerization partner ErbB3, to the apical cell surface, effectively segregating the two receptors. The apically located ErbB2 is phosphorylated on tyrosines 1139 and 1248. The phosphorylated ErbB2 in CACO-2 cells recruits the cytoplasmic adaptor protein Grb2, consistent with previous studies showing phosphotyrosine 1139 to be a Grb2 binding site. To address the issue of downstream signaling from apical ErbB2, we analyzed the three MAPK pathways of mammalian cells, Erk, p38, and JNK. Consistent with the more differentiated phenotype of the CACO-2 cells, p38 phosphorylation was robustly increased by Muc4 expression, with a consequent activation of Akt. In contrast, Erk and JNK phosphorylation was not changed. The ability of Muc4 to segregate ErbB2 and other ErbB receptors and to alter downstream signaling cascades in polarized epithelial cells suggests that it has a role in regulating ErbB2 in differentiated epithelia. INTRODUCTIONErbB2 is a 185-kDa class I receptor tyrosine kinase that is structurally related to the epidermal growth factor receptor EGFR. The ErbB family of receptors includes four members: epidermal growth factor receptor (EGFR, HER1, or c-ErbB1), c-ErbB2 (HER2, p185 neu ), c-ErbB3 (HER3), and c-ErbB4 (HER4) (Riese and Stern, 1998), which share 40 -45% sequence identity (Stein and Staros, 2000). The ErbB receptor extracellular domains are composed of four subdomains, which in order from the N-terminus are known as I (L1), II (CR1), III (L2), and IV (CR2) (Bajaj et al., 1987;Lax et al., 1988;Ward et al., 1995); subdomains I and III and subdomains II and IV are homologous. ErbB ligand binding is mediated primarily by subdomain III, and to a lesser extent by subdomain I (Lax et al., 1989;Khoda et al., 1993). Subdomains II and IV mediate the formation of specific ErbB homo and heterodimers (Garrett et al., 2002;Ogiso et al., 2002). The extracellular domain is followed by a transmembrane domain, a tyrosine kinase domain, and a segment of variable length of ϳ200 amino acids containing several tyrosine phosphorylation sites. On activation, these phosphotyrosines become docking sites for cytoplasmic signaling proteins that, in turn, initiate characteristic downstream signaling events (Klapper et al., 2000). The pathways activated may lead the cell to proliferation, differentiation, or apoptosis (Alroy and Yarden, 1997;Riese and Stern, 1998). All ErbB family members, with the exception of ErbB2, have high-affinity soluble ligands that induce receptor homo-or heterodimer formation and phosphorylation and trigger downstream signaling. The preferred ErbB heterodimer partner is ErbB2, and the ErbB2-ErbB3 pair generates the strongest proliferative signal, even...

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“…In contrast, we previously showed that expression of Muc4 in these cells results in a relocation of ErbB2 from the lateral to the apical surface (Ramsauer et al, 2003).…”

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confidence: 92%

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confidence: 99%

Muc4–ErbB2 Complex Formation and Signaling in Polarized CACO-2 Epithelial Cells Indicate That Muc4 Acts as an Unorthodox Ligand for ErbB2

Palau

Pino

Farooq

et al. 2006

MBoC

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“…HER2 stably interacts with the membrane mucin Muc4. The interaction is mediated through one of two EGF-like domains in Asialoglycoprotein-1 (ASPG-1), the membrane-associated subunit of Muc4 and may play a role in regulating the polar localization of HER2 (Carraway et al, 1999;Ramsauer et al, 2003). The experimental induction of Muc4 expression in cells lacking Muc4 leads to increase cell surface retention of HER2 and HER3 and increased HER2-HER3-signaling activity (Funes et al, 2006) (Figure 3).…”

Section: Cell Cycle Deregulationmentioning

confidence: 99%

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

2007

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“…Second, while the role of ERBB2 phosphorylation seems important, it is probably not the only factor involved in trastuzumab response. ERBB2-associated proteins may influence trastuzumab efficiency: receptors of the ERBB family (Diermeier et al, 2005), membrane receptors coregulated with ERBB2 such as CD44 (Wobus et al, 2001;Ghatak et al, 2005), CXCR4 (Li et al, 2004) and MUC4 (Ramsauer et al, 2003;Nagy et al, 2005), proteins of the ERBB2 signaling or endocytic pathways, or from cross-talking pathways (Nahta et al, 2006). Inactivation of PTEN, a cytoplasmic lipid-associated phosphatase involved in the AKT survival pathway, contributes to trastuzumab resistance (Nagata et al, 2004).…”

Section: Further Considerationsmentioning

confidence: 99%

ERBB2 phosphorylation and trastuzumab sensitivity of breast cancer cell lines

et al. 2007

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Breast cancers that overexpress the ERBB2 tyrosine kinase receptor may be treated with the recombinant humanized monoclonal anti-ERBB2 antibody trastuzumab (herceptin). However, resistance to this targeted therapy is frequent. We have determined the response of 18 breast tumor cell lines to trastuzumab and compared it with the ERBB2 phosphorylation status using antibodies directed against tyrosine residue 1248. We show that sensitivity to trastuzumab is frequently associated with the expression of a phosphorylated ERBB2 protein.

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Muc4/Sialomucin Complex, the Intramembrane ErbB2 Ligand, Translocates ErbB2 to the Apical Surface in Polarized Epithelial Cells

Cited by 78 publications

References 26 publications

Muc4–ErbB2 Complex Formation and Signaling in Polarized CACO-2 Epithelial Cells Indicate That Muc4 Acts as an Unorthodox Ligand for ErbB2

Muc4–ErbB2 Complex Formation and Signaling in Polarized CACO-2 Epithelial Cells Indicate That Muc4 Acts as an Unorthodox Ligand for ErbB2

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

ERBB2 phosphorylation and trastuzumab sensitivity of breast cancer cell lines

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