title: Unravelling the Mechanism of TrkA-Induced Cell Death by Macropinocytosis in Medulloblastoma Daoy Cells.
abstract: 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.
authors: Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada.
authors: Chunhui
authors: C
authors: Li
authors: Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada.
authors: James I S
authors: JI
authors: MacDonald
authors: Department of Biochemistry, Western University, London, Ontario, Canada.
authors: Asghar
authors: A
authors: Talebian
authors: Department of Biochemistry, Western University, London, Ontario, Canada.
authors: Jennifer
authors: J
authors: Leuenberger
authors: Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada.
authors: Claudia
authors: C
authors: Seah
authors: Robarts Research Institute, Schulich School of Medicine, Western University, London, Ontario, Canada Department of Clinical Neurological Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.
authors: Stephen H
authors: SH
authors: Pasternak
authors: Départment de Biochimie, Université de Montreal, Montreal, Quebéc, Canada.
authors: Stephen W
authors: SW
authors: Michnick
authors: Department of Biochemistry, Western University, London, Ontario, Canada Graduate Program in Neuroscience, Western University, London, Ontario, Canada smeakin@uwo.ca.
authors: Susan O
authors: 0000-0003-2469-6615
authors: SO
authors: Meakin
mesh_terms: D000199:Actins / Q000378:metabolism; D047389:Casein Kinase I / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D010766:Phosphorylation; D010873:Pinocytosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; C000611485:NTRK1 protein, human; C066737:RHOA protein, human; D012694:Serine; D020917:Receptor, trkA; D047389:Casein Kinase I; D016283:Proto-Oncogene Proteins p21(ras); D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein