Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27kip, but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways

Abstract

Muc4/sialomucin complex (SMC) is a multifunctional glycoprotein complex which can repress apoptosis in transfected tumor cells. Its transmembrane subunit acts as an intramembrane ligand for the receptor tyrosine kinase ErbB2 to induce the phosphorylation of ErbB2 and, by acting synergistically with the ErbB3 ligand neuregulin, can potentiate the phosphorylation of ErbB2 and ErbB3. In the present study we show that Muc4/ SMC alone robustly induces the phosphorylation of ErbB2 to enhance the tyrosine phosphate epitope (Tyr1248) recognized by anti-phospho-ErbB2. Although this tyrosine phosphorylation has been implicated in cell transformation, it does not activate any of the three mitogen-activated protein kinases (MAPKs) or protein kinase B/Akt of the phosphatidyl inositol 3-kinase pathway. Instead, Muc4/SMC expression induces upregulation of the cell cycle inhibitor p27 kip , consistent with the expression of Muc4/SMC in differentiated, rather than proliferative, epithelial cells. Interestingly, a combination of Muc4/SMC and neuregulin downregulate p27 kip and activate protein kinase B/Akt. These observations suggest that Muc4/SMC acts as a regulator of differentiation by inducing a limited phosphorylation of ErbB2 and a modulator of proliferation when acting synergistically with neuregulin to induce a more extensive phosphorylation on both ErbB2 and ErbB3.

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

“…5, merge). These results confirm our previous studies, which indicate that formation of the Muc4/SMC-ErbB2 complex leads to specific phosphorylation of the ErbB2 (26).…”

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

“…S Inaguma et al kinase signaling pathway (Schroeder et al, 2001;Jepson et al, 2002). However, despite the fact that increased MUC5AC expression correlates with a worse prognosis for patients with lung adenocarcinoma (Yu et al, 1996(Yu et al, , 2005, cholangiocarcinoma (Boonla et al, 2003;Aishima et al, 2006) and PDA (Takikita et al, 2009), a molecular mechanism for MUC5AC in determining the properties of these cancer cells has not been fully elucidated.…”

“…For instance, the expressions of MUC1, MUC2 and MUC5AC were statistically associated with a shorter survival time for pancreatic cancer patients in the United States (Takikita et al, 2009), suggesting that mucin functions not only to protect the normal epithelial surface from harsh environments but also to regulate cancer cell properties. Indeed, membrane-associated mucins were recently shown to play a crucial role in signal transduction (Schroeder et al, 2001;Jepson et al, 2002;Wen et al, 2003;Hollingsworth and Swanson, 2004;Bafna et al, 2010). However, the role for gel-forming mucins in cancer cells is not fully understood.…”

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

“…In other studies, sialo-mucin complex (SMC), a rat homologue of MUC4 has also been shown to play multiple roles in tumour cell biology. SMC/Muc4 acts as a ligand for ErbB2/HER2 inducing its limited phosphorylation (Jepson et al, 2002). The overexpression of SMC results in the suppression of both cell adhesion and immune killing of tumour cells, enhanced tumour growth and potentiation of metastasis (Komatsu et al, 1999(Komatsu et al, , 2000(Komatsu et al, , 2001.…”