Unravelling the Mechanism of TrkA-Induced Cell Death by Macropinocytosis in Medulloblastoma Daoy Cells

Macropinocytosis is a normal cellular process by which cells internalize extracellular fluids and nutrients from their environment and is one strategy that Ras-transformed pancreatic cancer cells use to increase uptake of amino acids to meet the needs of rapid growth. Paradoxically, in non-Ras trans...

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Bibliographic Details
Published in:	Molecular and cellular biology Vol. 36; no. 20; pp. 2596 - 2611
Main Authors:	Li, Chunhui, MacDonald, James I. S., Talebian, Asghar, Leuenberger, Jennifer, Seah, Claudia, Pasternak, Stephen H., Michnick, Stephen W., Meakin, Susan O.
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 15-10-2016 American Society for Microbiology
Subjects:	Actins - metabolism Casein Kinase I - metabolism Cell Death Cell Line, Tumor Cerebellar Neoplasms - metabolism Humans Medulloblastoma - metabolism Phosphorylation Pinocytosis Proto-Oncogene Proteins p21(ras) - metabolism Receptor, trkA - metabolism rhoA GTP-Binding Protein - metabolism rhoB GTP-Binding Protein - metabolism Serine - metabolism Signal Transduction
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Summary:	Macropinocytosis is a normal cellular process by which cells internalize extracellular fluids and nutrients from their environment and is one strategy that Ras-transformed pancreatic cancer cells use to increase uptake of amino acids to meet the needs of rapid growth. Paradoxically, in non-Ras transformed medulloblastoma brain tumors, we have shown that expression and activation of the receptor tyrosine kinase TrkA overactivates macropinocytosis, resulting in the catastrophic disintegration of the cell membrane and in tumor cell death. The molecular basis of this uncontrolled form of macropinocytosis has not been previously understood. Here, we demonstrate that the overactivation of macropinocytosis is caused by the simultaneous activation of two TrkA-mediated pathways: (i) inhibition of RhoB via phosphorylation at Ser 185 by casein kinase 1, which relieves actin stress fibers, and (ii) FRS2-scaffolded Src and H-Ras activation of RhoA, which stimulate actin reorganization and the formation of lamellipodia. Since catastrophic macropinocytosis results in brain tumor cell death, improved understanding of the mechanisms involved will facilitate future efforts to reprogram tumors, even those resistant to apoptosis, to die.
Bibliography:	Citation Li C, Macdonald JIS, Talebian A, Leuenberger J, Seah C, Pasternak SH, Michnick SW, Meakin SO. 2016. Unravelling the mechanism of TrkA-induced cell death by macropinocytosis in medulloblastoma Daoy cells. Mol Cell Biol 36:2596–2611. doi:10.1128/MCB.00255-16. Present address: Asghar Talebian, University of Texas Southwestern Medical Center, Dallas, TX, USA; Jennifer Leuenberger, Canadawide Scientific, Ottawa, Ontario, Canada.
ISSN:	1098-5549 0270-7306 1098-5549
DOI:	10.1128/MCB.00255-16