Frohman Lab
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The Frohman Laboratory
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| Research Interests | Selected Publications | CMM |
| Molecular Cloning Facility | Current Lab Members | Fomer Lab Members |
Regulation of exocytosis, cell shape, and mitochondrial fusion by lipid signaling pathways
Our laboratory examines lipid signals that alter cell morphology, regulate mitochondrial fusion, and trigger subcellular trafficking of membrane vesicles during regulated exocytosis and endocytosis. Disease-related topics include neurodegenerative disease (Charcot-Marie Tooth syndrome), diabetes, cancer, and impaired phagocytic immune responses to pathogens.
The specific topic constitutes study of signaling pathways mediated by members of the superfamiles of enzymes known as Phospholipase D (PLD) and PI4P Kinase. Classic PLD is activated by a wide variety of agonists that signal through G-protein coupled or tyrosine kinase receptors. PLD has varied cellular roles including facilitating membrane vesicle trafficking and fusion of the vesicles into the plasma membrane during regulated exocytosis, and reorganizing the actin cytoskeleton. We are currently investigating roles for PLD and PI4P lipid kinase in actin cytoskeleton reorganization, myoblast differentiation and fusion, Glut-4 glucose transporter translocation, phagocytosis, and regulated exocytosis (insulin and histamine release). In addition, we are exploring a novel member of the PLD superfamily that localizes to mitochondria and regulates fusion, and the mechanisms through which diminished rates of fusion cause neurodegenerative disease.
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Title |
Name |
Degree |
Project |
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Principal |
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MD, PhD, U. Penn. |
Making lab members feel happy about working hard |
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Senior Research Support Specialist |
Yelena
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MS, College of Chemistry & Pharmacology, |
Lab manager and Supervisor, Molecular Cloning Facility |
2-1477 |
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Administrative Assistant |
Jon Wood
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BA, SUNY at Stony Brook |
Administration |
Phone: (631) 632-1634 |
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Postdoctoral Fellow |
Phyllis Tsang
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MRI imaging of pancreatic beta-cells |
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| Postdoctoral Fellow | Xiao Xue (Sherry) Peng | Ph.D., Shanghai U. | Structural biology of MitoPLD | snowborn1122@hotmail.com |
| Postdoctoral Fellow | Qin (Grace) Chen | Shanghai Institute of Materia Medica | Functional roles for PLD | qin@pharm.stonybrook.edu |
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Postdoctoral Fellow |
Qun Gao |
Ph.D., New York Medical College |
Imaging Mitochondrial fusion |
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Graduate |
Mary Osisami
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BS, SUNY Stony Brook |
Functional analysis of PLD superfamily proteins |
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Postdoctoral Fellow |
Wenjuan Su
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Ph.D., Stony Brook University |
Phosphoinositides and phagocytosis; PLD inhibitor |
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Graduate |
Huiyan Huang
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BS, Fudan Univ., |
Mitochondrial fusion |
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Graduate |
Oladapo Yeku
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BS, Medgar Evers College |
Mitochondrial fusion and disease |
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| Graduate student | Wahida Ali | B.S. SUNY Binghamton | PLD roles in phagocytosis | Ali@pharm.sunysb.edu |
| Graduate student (mentor, Dr. Guangwei Du) | Akua Bonsra-Roach | B.S. Stony Brook University | PIP Kinases and PA | Bonsra@pharm.sunysb.edu |
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Past Title |
Name |
Current Position |
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Technician |
Ritu Goyanka |
Graduate Student, NYU |
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Wei Ao |
Technician, SUNY Stony Brook |
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Post-docs |
Olga E. Redina |
Assoc.. Prof., U. Novosibirsk, Russia |
oredina@yahoo.com |
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Juan A. Crosby |
Post-doc., UMDNJ, Newark, NJ |
crosbyja@umdnj.edu |
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Hilde Janssens |
FlyMine Administrator, England |
hildejj@gmail.com |
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Guangwei Du |
Assistant Professor, University of Texas at Houston |
Guangwei.Du@uth.tmc.edu |
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Gary Jenkins |
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Xiao Yu |
Post-doc., Indiana University |
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| Ping Huang | Instructor, Harvard University | phuang@enders.tch.harvard.edu | |
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Grad. Students |
William C. Colley |
Post-doc., St. Judes Hospital, Memphis, TN |
Mary-Ann.Bjornsti@stjude.org |
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Tsung-Chang Sung |
Post-doc., The Salk Institute |
Sung@pblserver.salk.edu |
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Yue Zhang |
Post-doc., SUNY Stony Brook |
yzhang@ms.cc.sunysb.edu |
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Suyong Yun |
Clinical pharmacology and discovery medicine investigator |
suyongyun@yahoo.com |
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Si Wu |
Graduate Student, Computer Science, SUNY Stony Brook |
siwu@ic.sunysb.edu |
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Danxia Ke |
Memorial Sloan-Kettering Cancer Center, New York, NY |
danshia@yahoo.com |
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Nianzhou Xiao |
Medical Residency |
xiaonz@yahoo.com |
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Margie LaLonde |
Resident, Fast-track program in Psychiatry, Columbia University |
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Seok-Yong Choi |
Assistant Professor Chonam University, South Korea |
seokyong@jnu.ac.kr |
| Elizabeth Scotto-Lavino | Post-doc, BNL | escotto@bnl.gov |
Nishikimi, A., Fukuhara,H., Su, W., Hongu, T., Takasuga, S., Mihara, H., Cao, Q., Sanematsu, F., Kanai, M., Hasegawa, H., Tanaka, Y., Shibasaki, M., Kanaho, Y., Sasaki, T., Frohman, M.A., and Fukui, Y. (2009) Sequential Regulation of DOCK2 Dynamics by Two Phospholipids during Neutrophil Chemotaxis. Science, 324:384-7.
Su, W., Yeku, O., Olepu, S., Genna, A., Park, J.-S., Ren, H., Du, G., Gelb, M.H., Morris, A.J., and Frohman, M.A. (2009) FIPI, a pan-Phospholipase D pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol. Pharm. 75: 437-46.
Du, G. and Frohman, M.A. (2009) A lipid-signaled myosin phosphatase surge disperses cortical contractile force early in cell spreading. Molecular Biology of the Cell, 20:200-8.
Lu, J., Fan, T., Zhao, Q., Zeng, W., Zaslavsky, E., Chen, J.J., Frohman, M.A., Golightly, M.G., Madajewicz, S., and Chen, W.-T. (2009) Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. International Journal of Cancer, in press.
Hauff, K.D., Choi, S.-Y., Frohman, M.A. and Hatch, G.M. (2009) Cardiolipin synthesis is required to support human cholesterol biosynthesis from palmitate upon serum removal in Hela cells. The Canadian Journal of Physiology and Pharmacology, in press.
Yeku., O. and Frohman, M.A. (2009) Cloning full-length cDNAs using Rapid Amplification of cDNA Ends (RACE). RNA. in press.
Su, W. and Frohman, M.A. Phospholipase D. (2009) In Lipid-derived Second Messengers, in Handbook of Cell Signaling, eds. Cantley, L. in press.
Frohman, M.A. and Tsirka, S.E. (2009) Polymerase Chain reaction: specialized applications. In: Nature Encylopedia of Life Sciences (Robertson, S., Editor). Macmillan, London. In press.
Su, W., Chen, Q., and Frohman, M.A. (2009) The potential for Phospholipase D inhibition as a therapeutic approach. Future Oncology, in press.
Huang, H. and Frohman, M.A. Lipid signaling on the mitochondrial surface. (2009) In Phospholipase D, BBRC special issue. Eds. Frohman M.A., and Cockcroft, S. in press.
Osisami, M. Huang, H., and Frohman, M.A. (2009) Lipid sensors in endocrine cell signaling. Molecular Endocrinology. In press.
Yeku., O., Scotto-Lavino, E., and Frohman, M.A. (2009) Identification of Alternative transcripts using Rapid Amplification of cDNA Ends (RACE). Molecular Endocrinology. In press.
Yang, J.-S., Gad, H., Lee, S., Mironov, A., Zhang, L., Beznoussenko, G.V., Valente, C., Turacchio, G., Bonsra, A.N., Du, G., Baldanzi, G., Graziani, A., Bourgoin, S., Frohman, M.A., Luini, A., and Hsu, V.W. (2008) COPI vesicle fission: a role for phosphatidic acid and insight into Golgi maintenance. Nature Cell Biology, 10:1146-53.
Zhao, C., Du, G., Frohman, M.A., and Bar-Sagi, D. (2007) Phospholipase D2-generated PA couples EGFR stimulation to Ras activation by Sos. Nature Cell Biology, 9:707-712.
Choi, S.-Y., Gonzalvez, F., Jenkins, G.M., Slomianny, C., Chretien, D., Arnoult, D., Petit, P.X., and Frohman, M.A. (2007) Cardiolipin deficiency releases cytochrome c from the inner mitochondrial membrane and accelerates stimuli-elicited apoptosis. Cell Death and Differentiation, 14:597-606.
Kobayashi-Nakano, A., Yamazaki, M. Unoki, T., Hongu, T., Murata, C., Taguchi, R., Katada, T., Frohman, M.A., Yokozeki, T., and Kanaho, Y. (2007) Role of AP-2 complex activation of phosphatidylinositol 4-phosphate 5-kinase g661 in synaptic vesicle endocytosis. EMBO J. 26:1105-16.
Zeniou-Meyer, M., Zabari, N., Ashery, U., Chasserot-Golaz, S., Haeberlé, A.-M., Demais, V., Bailly, Y., Gottfied, I., Nakanishi, H., Neiman, A.M., Du, G., Frohman, M.A., Bader, M.-B., and Vitale, N. (2007) PLD1 production of phosphatidic acid at the plasma membrane promotes exocytosis of large dense-core granule at a late stage. J. Biol. Chem., 282:21746-57.
Pannequin, J., Delaunay, N., Darido, C., Maurice, T., Crespy, P., Frohman, M.A., Matter, K., Bourgaux, J.-F., Bali, J.P., and Hollande, F. (2007) Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure. Molecular Cancer Research, 5:1147-57.
Choi, S.-Y., Huang, P., Jenkins, G.M., Chan, D.C., Schiller, J., and Frohman, M.A. (2006) A common signaling lipid requirement for Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nature Cell Biology, 8:1255-62.
Scotto-Lavino, E., Du, G., and Frohman, M.A. 5' end cDNA amplification using classic RACE (2006) Nature Protocols, 1:2555-62.
Scotto-Lavino, E., Du, G., and Frohman, M.A. Using 3’ RACE to clone cDNA ends. (2006) Nature Protocols, 1:2742-5.
Scotto-Lavino, E., Du, G., and Frohman, M.A. Amplification of 5’ end cDNA with ‘New RACE’. (2006) Nature Protocols, 1:3056-61.
LaLonde, M., Janssens, H., Yun, S., Crosby, J., Redina, O., Du, G., Olive, V., Choi, S.-Y., Altshuller, Y.M., Gergen, J.P., and Frohman, M.A. (2006) Phospholipase D is required for the progression of cellularization in Drosophila and functions by regulating vesicle trafficking. BMC Developmental Biology, 6:60.
Du. G., Yonekubo, J., Zeng, Y., Osisami, M., and Frohman, M.A. (2006) Design of small-hairpin RNA expression vectors based on miRNAs and RNA splicing. FEBS J., 273:5421-7.
Vicogne, J., Vollenweider, D., Smith, J., Huang, P., Frohman, M. and Pessin, J. (2006) Asymmetric phospholipid distribution drives in vitro reconstituted SNARE-dependent membrane fusion. Proc Natl Acad Sci U.S.A., 103:14761-6
Cai D, Netzer WJ, Zhong M, Lin Y, Du G, Frohman M, Foster DA, Sisodia SS, Xu H, Gorelick FS, Greengard P (2006). Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation. Proc Natl Acad Sci U S A. 103 1941-6.
Corrotte M, Chasserot-Golaz S, Huang P, Du G, Ktistakis NT, Frohman MA, Vitale N, Bader MF, Grant NJ (2006). Dynamics and function of phospholipase D and phosphatidic acid during phagocytosis. Traffic 7 365-77.
Suzuki T, Kanai Y, Hara T, Sasaki J, Sasaki T, Kohara M, Maehama T, Taya C, Shitara H, Yonekawa H, Frohman MA, Yokozeki T, Kanaho Y (2006). Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development. Mol Cell Biol. 26 6149-56.
Huang P, Jiang Z, Teng S, Wong YC, Frohman MA, Chung SK, Chung SS (2006). Synergism between phospholipase D2 and sorbitol accumulation in diabetic cataract formation through modulation of Na,K-ATPase activity and osmotic stress. Exp Eye Res .
Andersson L, Bostrm P, Ericson J, Rutberg M, Magnusson B, Marchesan D, Ruiz M, Asp L, Huang P, Frohman MA, Born J, Olofsson SO (2006). PLD1 and ERK2 regulate cytosolic lipid droplet formation. J Cell Sci. 119 2246-57.
Jenkins GM, Frohman MA. (2005) Phospholipase D: a lipid centric review. Cell Mol Life Sci. 62(19-20):2305-16.
Xiao N, Du G, Frohman MA. (2005) Peroxiredoxin II functions as a signal terminator for H2O2-activated phospholipase D1. FEBS J. 272(15):3929-37.
LaLonde, M.M., Janssen, H., Rosenbaum, E., Choi, S.-Y., Gergen, J.P., Colley, N.J., Stark, W.S., and Frohman, M.A.(2005) Regulation of phototransduction responsiveness and retinal degeneration by a phospholipase D-generated signaling lipid. J. Cell Biol. 169(3):471-9.
Huang, P., Altshuller, Y.M., Hou, J.C., Pessin, J.E., and Frohman, M.A. (2005) Insulin-stimulated plasma membrane fusion of Glut4 glucose transporter-containing vesicles is regulated by Phospholipase D1. Mol. Biol. Cell,. 16(6):2614-23.
Hughes WE, Elgundi Z, Huang P, Frohman MA, Biden TJ (2004). Phospholipase D1 regulates secretagogue-stimulated insulin release in pancreatic beta-cells. J Biol Chem. 279 27534-41.
Watanabe H, Yamazaki M, Miyazaki H, Arikawa C, Itoh K, Sasaki T, Maehama T, Frohman M.A., Kanaho Y. (2004)Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1-stimulated neurite outgrowth of cerebellar granule neurons. J Neurochem. 89(1):142-51.
Zhang Y, Huang P, Du G, Kanaho Y, Frohman M.A., Tsirka SE. (2004) Increased expression of two phospholipase D isoforms during experimentally induced hippocampal mossy fiber outgrowth. Glia. 46(1):74-83.
Du G, Huang P, Liang BT, Frohman M.A. (2004) Phospholipase D2 Localizes to the Plasma Membrane and Regulates Angiotensin II Receptor Endocytosis. Mol Biol Cell. 2004 Mar;15(3):1024-30.
Zheng XL, Gui Y, Du G, Frohman M.A., Peng DQ. (2004) Calphostin-C induction of vascular smooth muscle cell apoptosis proceeds through phospholipase D and microtubule inhibition. J Biol Chem. 279(8):7112-8.
Fang Y, Park IH, Wu AL, Du G, Huang P, Frohman M.A., Walker SJ, Brown HA, Chen J. (2003) PLD1 Regulates mTOR Signaling and Mediates Cdc42 Activation of S6K1. Curr Biol. 13:2037-44.
Huang, P. and Frohman, M.A. (2003) Phospholipase D and Glut-4 trafficking. Diabetes Metab Res Rev. 19:456-63
Ballou LM, Jiang YP, Du G, Frohman M.A., Lin RZ. (2003) Ca(2+)- and phospholipase D-dependent and -independent pathways activate mTOR signaling. FEBS Lett. 550:51-6.
Du, G., Altshuller, Y.M., Vitale, N., Huang, P., Chasserot-Golaz, S., Morris, A.J., Bader, M.-F., and Frohman, M.A. (2003) Regulation of Phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs. J.Cell Biol. 162(2):305-15
Du, G., Morris, A.J., Sciorra, V.A., and Frohman, M.A. (2002) G-protein coupled receptor regulation of Phospholipase D. In : G-protein Pathways. Methods in Enzymology (Hildebrandt, J.D. and Iyengar, R., Editor). 345:265-274.
Yamazaki, M., Miyazaki, H., Watanabe, H., Maehama, T., Frohman, M.A., and Kanaho, Y. (2002) Phosphatidylinositol 4-phosphate 5-kinase couples ROCK to neurite remodeling. J. Biol. Chem, 277:17226-17230.
Choi., W.S., Kim, Y.M., Combs, C., Frohman, M.A., and Beaven, M.A. (2002) Phospholipase D1 and 2 Regulate Different Phases of Exocytosis in Mast Cells. J. Immunology 168:5682-9.
Vitale, N., Chasserot-Golaz, S., Bailly, Y., Morinaga, N., Frohman, M.A., and Bader, M.-F. (2002) Calcium-regulated exocytosis of dense core vesicles requires the activation of ARF6 by ARNOat the plasma membrane. J. Cell Biol. 159:79-89.
Denmat-Ouisse LA, Phebidias C, Honkavaara P, Robin P, Geny B, Min do S, Bourgoin S, Frohman MA, Raymond MN. (2001) Regulation of constitutive protein transit by phospholipase D in HT29-cl19A cells. J. Biol.Chem. 276:48840-6.
Vitale, N., Caumont-Primus, A.-S., Chasserot-Golaz, S., Du, G., Wu, S., Sciorra, V.A., Morris, A.J., Frohman, M.A. and Bader, M.-F. (2001) Phospholipase D1 : a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J., 20(10):2424-2434.
Freyberg, Z., Siddhanta, A., Sweeney, D., Bourgoin, S., Frohman, M.A., and Shields, D. (2001) Intracellular Localization of Phospholipase D1 in Mammalian Cells. Mol. Biol. Cell., 12(4):943-955.
Humeau, Y., Vitale, N., Chasserot-Golaz, S., Dupont, J.-L., Du, G., Frohman, M.A., Bader, M.-F. and Poulain, P. (2001) A role for phospholipase D1 in neurotransmitter release. Proc. Natl. Acad. Sci. U.S.A.. 98:15300-5.
Du, G., Altshuller, Y.M., Kim., Y., Han, J.M., Ryu, S.H., Morris, A.J., and Frohman, M.A. (2000) Dual requirement for Rho and protein kinase C in direct activation of phospholipase D1 through G-protein coupled receptor signaling. Mol. Biol. Cell., 11:4359-4368.
Slaaby, R., Du, G., Altshuller, Y. M., Frohman, M.A., and Seedorf, K. (2000) PKCa and PLCg are involved in the activation of PLD1 and PLD2 upon insulin stimulation. Biochem. J., 351:613-619.
Zhang, Y., Redina, O., Altshuller, Y.M., Yamazaki, M., Ramos, J., Chneiweis, H., Kanaho, Y., and Frohman, M.A. (2000) Regulation of PLD1 and PLD2 expression levels by Pea-15, a novel PLD-interacting protein. J. Biol. Chem., 275: 35224-35232.
Park, J.B., Kim, J.H., Kim, J.H., Kim, J, Yoo, J.-S.,Suh, P.-G., Du, G., Frohman, M.A., and Ryu, S.H. (2000) Cardiac phospholipase D2 localizes to sarcolemmal membranes and is inhibited by alpha-actinin in an ADP-ribosylation factor-reversible manner. J. Biol. Chem., 275: 21295-21301.
Lee, C., Kim, S.R., Chung, J.-K., Frohman, M.A., Kilimann, M.W., Rhee, S.G. (2000) Inhibition of Phospholipase D by Amphiphysins. J. Biol. Chem., 275: 18751-18758.
Wu, Y.P., Lu, W., Sung, T-C., Frohman, M.A., Milev, P., Bugge, T.H., Degen, J.L.,Margolis, R.U., and Tsirka, S.E. (2000) The tPA/plasmin extracellular proteolytic system contributes to hippocampal mossy fiber reorganization through a novel proteoglycan substrate. J. Cell Biol., 148:1295-304.
Honda, A., Nogami, M., Yokozeki, T., Yamazaki, M., Nakamura, H., Watanabe, H., Kawamoto, K., Nakayama, K., Morris, A.J., Frohman, M.A., and Kanaho, Y. (1999) Phosphatidylinositol 4-phosphate 5-kinasea is a Downstream Effector of the Small G Protein ARF6 in Membrane Ruffle Formation. Cell, 99:521-532.
Sciorra, V.A, Rudge, S., Prestwich, G.D., Frohman, M.A., Engebrecht, J., and Morris, A.J. (1999) Identification of a phosphoinositide binding motif that mediates activation of mammalian and yeast Phospholipase D isoenzymes. EMBO J., 18: 5911-5921.
Zhang, Y, Altshuller, Y.A., Morris, A.J., and Frohman, M.A. (1999) Loss of Receptor Regulation by a Phospholipase D1 mutant unresponsive to Protein Kinase C. EMBO J., 18:6339-6348.
Yamazaki, M., Zhang, Y., Watanabe, H., Yokozeki, T., Ohno, S., Kaibuchi, K., Shibata, H., Mukai, H., Ono, Y., Frohman, M.A., and Kanaho, Y. (1999) Identification of the RhoA-binding domain of Phospholipase D1. J. Biol. Chem., 274:6035-6038.
Rizzo, M.A., Shome, K., Vasudevan, C., Stolz, D.B., Sung, T.-C., Frohman, M.A., Watkins, S.C., and Romero, G. (1999)Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent Raf-1 translocation to the plasma membrane and the activation of the MAP kinase pathway. J. Biol. Chem., 274: 1131-1139.
Sung, T.-C., Altshuller, Y.M., Morris, A.J. and Frohman, M.A. (1999) Molecular Analysis of Mammalian Phospholipase D2. J. Biol. Chem. 274:494-502.
Sung, T.-C., Zhang, Y., Morris, A.J. and Frohman, M.A. (1999) Structural Analysis of Human Phospholipase D1. J. Biol. Chem., 274:3659-3666.
Sung, T.-C., Roper, K., Zhang, Y., Rudge, S., Temel, R., Hammond, S.M., Morris, A.J., Moss, B., Engebrecht, J., and Frohman, M.A. (1997) Mutagenesis of Phospholipase D defines a superfamily including a trans-Golgi viral protein required for poxvirus pathogenicity. EMBO J. 16:4519-4530.
Chong, J.A., Tapia-Ramírez, J., Kim, S., Toledo-Aral, J.J., Zheng, Y., Boutros, M.C., Altshuller, Y.M., Frohman, M.A., Kraner, S.D., and Mandel, G. (1995) REST: A Mammalian Silencer Protein that Restricts Sodium Channel Gene Expression to Neurons. Cell 80:949-957.