Beta-Arrestins act as signal terminators for G protein-coupled receptors; they have also been implicated as scaffolding proteins for Src and mitogen-activated protein kinase signaling pathways and transactivators of receptor tyrosine kinases, suggesting their possible role in development and oncogenic signaling. Dephosphorylation of serine 412 is necessary for Src and mitogen-activated protein kinase transactivation. We hypothesized that altered beta-arrestin 1 phosphorylation and activation status could play a role in gliomagenesis. Using monoclonal anti-phospho-(serine 412)- and total beta-arrestin 1 antibodies, we performed immunohistochemistry on 126 human glioma samples and 7 nonneoplastic controls and Western blot analysis on 5 glioblastomas and 5 nonneoplastic controls. We found high constitutive beta-arrestin 1 phosphorylation in nonneoplastic brain tissue, particularly in neurons and neuropil. Most Grade II and III gliomas retained high beta-arrestin 1 phosphorylation. By contrast, most of the glioblastoma samples (58/81) showed nearly complete beta-arrestin 1 dephosphorylation by immunohistochemistry and decreased relative phosphorylation by Western blot. Expression of constitutively activated epidermal growth factor receptor vIII in U251 cells caused decreased beta-arrestin 1 phosphorylation without altering total beta-arrestin 1 levels. These results suggest that beta-arrestin 1 dephosphorylation/inactivation is associated with aspects of the malignant behavior of glioblastomas.
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