Uteroglobin Binding Proteins: Regulation of Cellular Motility and Invasion in Normal and Cancer Cells

Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 02/2000; 923(1):234-48. DOI: 10.1111/j.1749-6632.2000.tb05533.x
Source: PubMed


Uteroglobin (UG) is a multifunctional, secreted protein with anti-inflammatory and antichemotactic properties. While its anti-inflammatory effects, in part, stem from the inhibition of soluble phospholipase A2 (sPLA2) activity, the mechanism(s) of its antichemotactic effects is not clearly understood. Although specific binding of UG on microsomal and plasma membranes has been reported recently, how this binding affects cellular function is not clear. Here, we report that recombinant human UG (hUG) binds to both normal and cancer cells with high affinity (20-35 nM, respectively) and specificity. Affinity cross-linking studies revealed that 125I-hUG binds to the NIH 3T3 cell surface with two proteins of apparent molecular masses of 190 and 49 kDa, respectively. UG affinity chromatography yielded similar results. While both the 190- and 49-kDa proteins were expressed in the heart, liver, and spleen, the lung and trachea expressed only the 190-kDa protein. Some cancer cells (e.g., mastocytoma, sarcoma, and lymphoma) expressed both the 190- and 49-kDa proteins. Further, using functional assays, we found that UG dramatically suppressed the motility and extracellular matrix invasion of both NIH 3T3 and some cancer cells. In order to further characterize the anti-ECM-invasive properties of UG, we induced expression of hUG into cancer cell lines derived from organs that, under physiological circumstances, secrete UG at a high level. Interestingly, it has been reported that a high percentage of the adenocarcinomas arising from the same organs fail to express UG. Our results on induced hUG expression in these cells show that inhibition of motility and ECM invasion requires the expression of both UG and its binding proteins. Taken together, our data define receptor-mediated functions of UG in which this protein regulates vital cellular functions by both autocrine and paracrine pathways.

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    • "Recently, we found that AF-1 specifically binds to a saturable membrane receptor, the UG receptor, and activates the MAPK signaling pathway [22]. Kundu and coworkers first identified the UG receptor in several types of cells; treating the cells expressing the UG receptor with UG dramatically suppressed cell growth and ECM invasion, but such treatment had no effect on cells lacking the UG receptor [5,31-33]. Subsequently, molecular cloning and analysis of the UG receptor cDNA indicated that it encodes a 55-kDa protein; on the basis of amino acid similarity, the UG receptor was classified in the lipocalin receptor family, which has remarkable functional diversity [34,35]. "
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