144 research outputs found
Co-opted integrin signaling in ErbB2-induced mammary tumor progression
Although almost two decades of study point to a central role for aberrant ErbB2 activation in breast cancer, many cellular and biochemical mechanisms underlying ErbB2-induced tumor initiation and progression remain to be resolved. A study by Guo et al. published recently in Cell indicates that the signaling function of β4 integrin actively contributes to the initiation, growth, and invasion of ErbB2-induced mammary tumors in transgenic mice by promoting the activation of c-Jun and STAT3. These observations offer novel mechanistic insight into ErbB2 action and highlight the notion that ErbB2 co-opts the functions of other signaling proteins to elicit tumor progression
Galectin-3 regulates intracellular trafficking of EGFR through Alix and promotes keratinocyte migration.
The EGFR-mediated signaling pathways are important in a variety of cellular processes, including cell migration and wound re-epithelialization. Intracellular trafficking of EGFR is critical for maintaining EGFR surface expression. Galectin-3, a member of an animal lectin family, has been implicated in a number of physiological and pathological processes. Through studies of galectin-3-deficient mice and cells isolated from these mice, we demonstrated that the absence of galectin-3 impairs keratinocyte migration and skin wound re-epithelialization. We have linked this pro-migratory function to a crucial role of cytosolic galectin-3 in controlling intracellular trafficking and cell surface expression of EGFR after EGF stimulation. Without galectin-3, the surface levels of EGFR are markedly reduced, and the receptor accumulates diffusely in the cytoplasm. This is associated with reduced rates of both endocytosis and recycling of the receptor. We have provided evidence that this previously unreported function of galectin-3 may be mediated through interaction with its binding partner Alix, which is a protein component of the ESCRT (endosomal sorting complex required for transport) machinery. Our results suggest that galectin-3 is potentially a critical regulator of a number of important cellular responses through its intracellular control of trafficking of cell surface receptors
The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells
Abstract Introduction Previous studies indicate that overexpression of the membrane-associated mucin MUC4 is potently anti-adhesive to cultured tumor cells, and suppresses cellular apoptotic response to a variety of insults. Such observations raise the possibility that MUC4 expression could contribute to tumor progression or metastasis, but the potential involvement of MUC4 in breast cancer has not been rigorously assessed. The present study aimed to investigate the expression of the membrane mucin MUC4 in normal breast tissue, primary breast tumors and lymph node metastases, and to evaluate the role of MUC4 in promoting the malignant properties of breast tumor cells. Methods MUC4 expression levels in patient-matched normal and tumor breast tissue was initially examined by immunoblotting lysates of fresh frozen tissue samples with a highly specific preparation of anti-MUC4 monoclonal antibody 1G8. Immunohistochemical analysis was then carried out using tissue microarrays encompassing patient-matched normal breast tissue and primary tumors, and patient-matched lymph node metastases and primary tumors. Finally, shRNA-mediated knockdown was employed to assess the contribution of MUC4 to the cellular growth and malignancy properties of JIMT-1 breast cancer cells. Results Immunoblotting and immunohistochemistry revealed that MUC4 levels are suppressed in the majority (58%, p < 0.001) of primary tumors relative to patient-matched normal tissue. On the other hand, lymph node metastatic lesions from 37% (p < 0.05) of patients expressed higher MUC4 protein levels than patient-matched primary tumors. MUC4-positive tumor emboli were often found in lymphovascular spaces of lymph node metastatic lesions. shRNA-mediated MUC4 knockdown compromised the migration, proliferation and anoikis resistance of JIMT-1 cells, strongly suggesting that MUC4 expression actively contributes to cellular properties associated with breast tumor metastasis. Conclusions Our observations suggest that after an initial loss of MUC4 levels during the transition of normal breast tissue to primary tumor, the re-establishment of elevated MUC4 levels confers an advantage to metastasizing breast tumor cells by promoting the acquisition of cellular properties associated with malignancy
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Multiple facets of sialomucin complex/MUC4, a membrane mucin and ErbB2 ligand, in tumors and tissues (Y2K update)
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Concanavalin a perturbation of membrane enzymes of mammary gland
The plant lectin concanavalin A (Con A) specifically inactivates the 5Ⲡânucleotidase of a plasma membraneâenriched fraction from lactating mammary gland. The lectin also causes an activation of the membrane Mg++ âATPase, but does not affect galactosyltransferase or alkaline phosphatase. The enzyme perturbations are prevented by Îąâmethylmannoside, an inhibitor of Con A binding, indicating that specific binding to carbohydrate structures rather than nonspecific proteinâprotein interaction is involved. Solubilization of the 5Ⲡânucleotidase in detergents (0.2% Triton Xâ100 or 1% deoxycholate) does not prevent Con A inactivation, indicating that incorporation into the membrane structure is not a requirement for the Con A effect. The results suggest that Con A inactivates the 5Ⲡânucleotidase by a direct interaction with the enzyme and that this enzyme is a Con A receptor site on the surface of mammary cells
Phenothiazine binding by a homolog of calpactin, the pp60src tyrosine kinase substrate
Microvilli isolated from 13762 mammary ascites tumor cells contain a major calciumâsensitive protein (AMVâp35) that can be isolated with microvillar microfilament cores prepared by Triton Xâ100 extraction in the presence but not absence of calcium. AMVâp35 can be readily purified from ethylene glycol bis(βâaminoethyl ether)âN,N,Nâ,Nââtetraacetic acid extracts of the microfilament cores by chromatography on an anion exchange column, to which it does not bind. Immunoblot analysis indicates that AMVâp35 is related to calpactin I, the pp60src tyrosine kinase substrate. In the presence of calcium, AMVâp35 binds approximately 4 mol of chlorpromazine per mole of protein in a binding process showing apparent positive cooperativity, similar to calmodulin; however, in contrast to calmodulin, AMVâp35 also binds phenothiazine in the absence of calcium.âCarraway, K. L., III; Liu, Y.; Puett, D; Carraway, K. L.; Carothers Carraway, C. A. Phenothiazine binding by a homolog of calpactin, the pp60src tyrosine kinase substrate. FASEB J. 1: 46â50; 1987
Thermodynamic characterization of the linked sign state and binding equilibria of five cytochromes -450 substrate analogs
Thesis (B.S.) in Biochemistry--University of Illinois at Urbana-Champaign, 1985.Includes bibliographical references
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