This proposal seeks to understand the role that the RalA/phospholipase D (PLD) signaling pathway plays in mitogenic signaling. The applicant's laboratory has demonstrated that PLD activity is elevated in cells treated with a variety of mitogenic stimuli, and that this pathway is a critical mediator of transformation by v-Src, v-Raf, v-Ras, and overexpression of the EGF receptor. In normal quiescent cells, PLD is complexed with GDP-bound RalA and localized to cellular membranes. The enzyme becomes activated upon RalA GTP exchange and recruitment of Arf GTP to the complex, both events thought to be brought about by activation of Ras. However, Arf GTP does not bind the RalA/PLD complex directly, and elevated PLD activity in membranes of Ras-transformed cells requires the addition of cytosol. These findings suggest that an additional factor is needed for complete activation of PLD. PLD hydrolyzes phosphatidylcholine to phosphatidic acid (PA). PA is involved in many biological processes, including intracellular vesicle formation and activation of signaling molecules, but its exact role in promoting mitogenic signaling is not understood. Preliminary evidence from the applicant's lab suggests that PLD may play a role in EGF receptor endocytosis.
Two aims are proposed to further investigate both the mechanism of PLD activation and its putative role in endocytosis.
The first aim i s to purify and characterize a recently discovered low molecular weight PLD-stimulating factor (PLD-SF) that is elevated in transformed and dividing cells.
The second aim will test the hypothesis that PLD regulates intracellular signaling by facilitating receptor-mediated endocytosis to generate """"""""signaling vesicles.""""""""
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| Patel, Deven; Menon, Deepak; Bernfeld, Elyssa et al. (2016) Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells. J Biol Chem 291:9322-9 |
| Mukhopadhyay, Suman; Frias, Maria A; Chatterjee, Amrita et al. (2016) The Enigma of Rapamycin Dosage. Mol Cancer Ther 15:347-53 |
| Saqcena, Mahesh; Patel, Deven; Menon, Deepak et al. (2015) Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle. Cell Cycle 14:2285-92 |
| Mukhopadhyay, Suman; Chatterjee, Amrita; Kogan, Diane et al. (2015) 5-Aminoimidazole-4-carboxamide-1-?-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells. Cell Cycle 14:3331-9 |
| LeGendre, Onica; Breslin, Paul As; Foster, David A (2015) (-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization. Mol Cell Oncol 2:e1006077 |
| Mukhopadhyay, Suman; Saqcena, Mahesh; Chatterjee, Amrita et al. (2015) Reciprocal regulation of AMP-activated protein kinase and phospholipase D. J Biol Chem 290:6986-93 |
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