Protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 functions as a growth suppressor in meningioma cells by activating Rac1-dependent c-Jun-NH(2)-kinase signaling.
Meningiomas are the second most common brain tumor in adults, yet comparatively little is presently known about the dysregulated growth control pathways involved in their formation and progression. One of the most frequently observed genetic changes in benign meningioma involves loss of protein 4.1B expression. Previous studies from our laboratory have shown that protein 4.1B growth suppression in meningioma is associated with the activation of the c-Jun-NH(2)-kinase (JNK) pathway and requires localization of a small unique region (U2 domain) of protein 4.1B to the plasma membrane. To define the relationship between protein 4.1B expression and JNK activation, as well as to determine the mechanism of JNK activation by protein 4.1B, we used a combination of genetic and pharmacologic approaches. In this report, we show that protein 4.1B/differentially expressed in adenocarcinoma of the lung-1 (DAL-1) expression in meningioma cells in vitro results in JNK activation, which requires the sequential activation of Src, Rac1, and JNK. In addition, inhibition of Rac1 or JNK activation abrogates protein 4.1B/DAL-1 growth suppression and cyclin A regulation. Last, protein 4.1B/DAL-1 regulation of this critical growth control pathway in meningioma cells requires the presence of the U2 domain. Collectively, these observations provide the first mechanistic insights into the function of protein 4.1B as a growth regulator in meningioma cells.
Gerber
Mark A
MA
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bahr
Scott M
SM
Gutmann
David H
DH
D048708:Cell Growth Processes / Q000502:physiology; D019925:Cyclin A / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008579:Meningioma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008840:Microfilament Proteins; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D019925:Cyclin A; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D008840:Microfilament Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D020830:rac1 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C116887:EPB41L3 protein, human; C107953:RAC1 protein, human