Muc4\sialomucin Complex, A Specific Intramembrane Modulator of ERBB2/HER2/NEU, Potentiates Primary Tumor Growth and Suppresses Apoptosis in A Xenotransplanted Melanoma.

Abstract

INTRODUCTION. Sialomucin complex (SMC/MUC4) is a large mucin-containing complex implicated in tumor progression. Overexpression of the membrane mucin MUC4/Sialomucin complex (SMC) has been observed during malignant progression of mammary tumors in both humans and rats, suggesting that deregulation of MUC4/SMC expression facilitates development of these malignancies. The complex, expressed preferentially in epithelial tissues and their tumors, was originally isolated from and characterized in the aggressive 13762 ascites rat mammary adenocarcinoma. SMC/Muc4 is a large, heterodimeric glycoprotein complex composed of two subunits, a heavily glycosylated mucin extracellular domain ASGP-1, stably associated with the N-glycosylated transmembrane subunit ASGP-2. The ASGP-2 sequence contains two EGF-like domains within the extracellular region, suggesting a potential ligand role; the characterization of an ASGP-2/ErbB2-containing signal transduction particle in the constitutively activated ascites cells provided support for this ligand hypothesis. Co-infection of insect cells with ASGP-2 and members of the EGFR family demonstrated that ASGP-2 binds selectively via EGF-1 to ErbB2, up-regulating the receptor’s kinase activity and receptor autophosphorylation; and modulating the effects of the soluble ligand NDF/HRG on the ErbB2/ErbB3 heterodimer. Previous studies have shown that overexpression of SMC in A375 melanoma cells causes increased tumor metastases when the cells were injected into nude mice. The present studies attempt to elucidate the role(s) of SMC in the potentiation of tumor cell survival and to determine the effect of overexpression of SMC on apoptosis in serum starved A375 melanoma cells.