Uteroglobin binding proteins: regulation of cellular motility and invasion in normal and cancer cells.
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.
Kundu
G C
GC
Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA. gopalkundu@hotmail.com
Zhang
Z
Z
Mantile-Selvaggi
G
G
Mandal
A
A
Yuan
C J
CJ
Mukherjee
A B
AB
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics*; D011869:Radioligand Assay / Q000706:statistics & numerical data; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D002352:Carrier Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014598:Uteroglobin