Faculty / Research

Michael A. Frohman, MD,PhD

Professor and Chair 

 

Director, Medical Scientist Training Program

Postdoctoral fellowship, University of California at San Francisco

M.D., Ph.D., University of Pennsylvania School of Medicine

B.S. with Distinction, High Honors in Chemistry and in Cellular & Molecular Biology, University of Michigan

michael.frohman@stonybrook.edu
Lipid Signaling: Roles in mitochondrial biology, spermatogenesis, diabetes, immune function, the CNS, platelet activation, and cancer; - Imaging Pancreatic β-cells using metabolomics and MRI.

Our lab explores roles for lipid signaling pathways in cellular and physiological settings. More specifically, we focus on functions mediated by members of the Phospholipase D (PLD), PI4P Kinase, and Lipin enzyme families. Areas of interest include:

 

-    Mitochondrial fusion & fission and the ability of mitochondria to serve as scaffolds for biogenesis of a specialized form of RNAi known as piRNA (1,2).

-    Subcellular trafficking of membrane vesicles during signaling-activated exocytosis and endocytosis (3,4).

-    Disease-related topics include neurodegeneration, diabetes, pathological thrombus formation, cancer, and impaired immune responses.

 

In a non-lipid signaling projected connected to diabetes, we are also developing methods to non-invasively image pancreatic b-cell mass using MRI and metabolomics.

Michael Frohman undertook training in a variety of disciplines including biochemistry, immunology, and developmental biology. During his postdoctoral fellowship, he developed the molecular biological technique known as “5’ RACE” which since has seen wide use, first in cDNA cloning and now in the cataloging of endogenous RNAi. The Frohman lab cloned the mammalian family of PLD isoforms in the mid-to-late ‘90s, and has since been exploring their function in numerous disease settings. Alumni of the Frohman lab have faculty positions in South Korea, Russia, and the USA.

Huang, H., Gao, Q. Peng, X.X., Choi, S.-Y., Sarma, K., Ren, H., Morris, A.J., and Frohman, M.A. (2011) piRNA-associated germline nuage formation and spermatogenesis require MitoPLD pro-fusogenic mitochondrial-surface lipid signaling. Developmental Cell, 20:376-387.

Huang, P., Yeku, O., Zong, H., Tsang, P., Su, W., Xu, X., Teng, S., Osisami, M., Kanaho, Y., Pessin, J.E., and Frohman, M.A. (2011) PI4P5-Kinase a deficiency alters dynamics of glucose-stimulated insulin release and protects against type 2 diabetes and obesity in mice. Diabetes,60:454-63.

Elvers et al., (2010) Impaired integrin aIIbb3 activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Science Signaling, 3:1-10.

Tsukahara et al. (2010) The novel second messenger Cyclic PA Negatively Regulates the Nuclear Hormone Receptor PPARγ. Molecular Cell, 39:421-32.

Dall’Armi, C., Hurtado-Lorenzo, A., Voronov, S.V., Yeku, O., Frohman, M.A., and Di Paolo, G. (2010) The Phospholipase D1 Pathway Modulates Macroautophagy. Nature Communications, 1:142-152.

Scotto-Lavino, E., Garcia-Diaz, M., Du, G., and Frohman, M.A. (2010) The basis for the isoform-specific interaction of Myosin Phosphatase subunits PP1c b and MYPT1. J. Biol. Chem., 285:6419-24.

Huang, H., Choi, S.-Y., and Frohman, M.A. (2010) A Quantitative Assay for Mitochondrial Fusion using Renilla Luciferase Complementation. Mitochondrion, 10:559-66.

Nishikimi et al. (2009) Sequential Regulation of DOCK2 Dynamics by Two Phospholipids during Neutrophil Chemotaxis. Science, 324:384-7.

Du, G. and Frohman, M.A. (2009) A lipid-signaled myosin phosphatase surge disperses cortical contractile force early in cell spreading. Mol. Biol. Cell, 1:200-8.

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 PLD pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol. Pharm. 75:437-46.

Yang, J.-S. et al. (2008) COPI vesicle fission: a role for phosphatidic acid and insight into Golgi maintenance. Nature Cell Biol., 10:1146-53.

Scotto-Lavino,E, Du,G, and Frohman,MA (2007) 5’ End cDNA Amplification using Classic RACE. Nature Protocols, 1:2555-2562.

Zhao, C., Du, G., Skowronek, K., Frohman, M.A., and Bar-Sagi, D. (2007) Phospholipase D2-generated PA couples EGFR stimulation to Ras activation by Sos. Nature Cell Biol, 9:707-12.

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 Biol., 8:1255-62.

LaLonde, M.M., Janssens, 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. 169:471-9.

Sasaki, J. et al. (2005) The phosphatidylinositol 4-phosphate 5-kinase PIPKIa is a negative regulator of anaphylaxis and FceRI signaling. J. Exp. Med., 201:859-70.

Huang, P., Altshuller, Y.M., Hou, J.C., Pessin, J.E., and Frohman, M.A. (2005) Insulin-stimulated plasma membrane fusion of the Glut4 glucose transporter is regulated by PLD1. Mol. Biol. Cell, 16:2614–23.

Du, G., Huang, P., Liang, B.T. and. Frohman, M.A. (2004) PLD2 localizes to the plasma membrane and regulates AgntII receptor endocytosis. Mol. Biol. Cell, 15:1024-30.

Du, G, Altshuller, YM, Vitale, N, Huang, P, Morris, AJ, Bader, MF, and Frohman, MA (2003) Regulation of PLD subcellular cycling through coordination of multiple membrane association motifs. J. Cell Biol 62:305-15.

Vitale, N., Caumont, A.S., Chasserot-Golaz, S., Wu, S., Zhang, Y., Morris, A.M., Frohman, M.A. and Bader, M.F (2001) PLD1: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J., 20:2424-34.

Zhang, Y, Altshuller, Y.A., Hammond, S.A., Hayes, F., Morris, A.J., and Frohman, M.A. (1999) Loss of Receptor Regulation by a PLD1 mutant unresponsive to Protein Kinase C.  EMBO J., 18:6339-6348.

Honda et al. (1999) Phosphatidylinositol 4-phosphate 5-kinasea is a Downstream Effector of the Small G Protein ARF6 in Membrane Ruffle Formation. Cell, 99:521–32.

Colley, W.C., Sung, T.-C., Roll, R., Jenco, J., Hammond, S.M., Altshuller, Y.M., Bar-Sagi, D., Morris, A.J., and Frohman, M.A. (1997) Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr. Biol. 7:191-201.

Sung et al. (1997) Mutagenesis of Phospholipase D defines a superfamily including a trans-Golgi viral protein required for poxvirus pathogenicity. EMBO J. 16:4519-4530.

Chong et al. (1995) REST:  A Mammalian Silencer Protein that Restricts Sodium Channel Gene Expression to Neurons. Cell 80:949-957.

Hammond, S.M., Altshuller, Y.M., Sung, T.-C., Rudge, S.A., Rose, K., Engebrecht, J., Morris, A.J, and Frohman, M.A. (1995) Human ARF-activated phosphatidylcholine-specific Phospholipase D Defines a New and Highly Conserved Gene Family. J. Biol. Chem. 270: 29640-43.

Frohman, M.A., Dush, M.K., and Martin, G.R. (1988). Rapid production of full-length cDNAs from rare transcripts by amplification using a single gene-specific oligonucleotide primer. PNAS 85:8998-9002.

Lab: 495 Center for Molecular Medicine

Phone: 631-632-1477

 

Yelena Altshuller                                    
Senior Research Support Specialist                       
yelena@pharm.stonybrook.edu

 

Supervisor, Molecular Cloning Facility                                                                                        mcs@pharm.stonybrook.edu

Grace (Qin) Chen        
                                        
Postdoctoral Fellow                                      
qin@pharm.stonybrook.edu

Qun Gao           
Postdoctoral Fellow           
qun@pharm.stonybrook.edu

Sherry (Xiaoxue) Peng           
Postdoctoral Fellow           
peng@pharm.stonybrook.edu

Devi Ekanayake           
Postdoctoral Fellow           
devi@pharm.stonybrook.edu

Wahida Ali           
Graduate student           
Ali@pharm.stonybrook.edu

Pheobe (Chai-Ying) Yang           
Graduate student           
chiabone@gmail.com

Rochelle Nelson           

Graduate student           
rochelle.k.nelson@gmail.com

Isaiah Schuster           
Post-bac student           
schuster.isaiah@gmail.com

Yorleny Vicioso           
Undergraduate           
yvicioso@notes.cc.sunysb.edu

The Frohman Laboratory

Research Interests   Selected Publications CMM
Molecular Cloning Facility Current Lab Members Fomer Lab Members

 



Research Interests:

 

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.

Lab Members:

TitleNameDegreeProject Phone#
Principal InvestigatorMichael Frohman
MD, PhD, U. Penn.Making lab members feel happy about working hard 
Sr. Research Support SpecialistYelena Altshuller
MS, College of Chemistry & Pharmacology,
St. Petersburg, Russia
Lab manager and Supervisor, Molecular Cloning Facility2-1477
Administrative Assistant Jon Wood
BA, SUNY at Stony BrookAdministration631-632-1634
Postdoctoral FellowPhyllis TsangPhD, Univ.of Hong KongMRI imaging of pancreatic beta-cells 
Postdoctoral FellowXiao Xue (Sherry) PengPh.D., Shanghai U.Structural biology of MitoPLD 
Postdoctoral FellowQin (Grace) ChenShanghai Institute of Materia MedicaFunctional roles for PLD 
Postdoctoral FellowQun GaoPh.D., New York Medical CollegeImaging Mitochondrial fusion 
Graduate StudentMary Osisami
BS, SUNY Stony Brook Functional analysis of PLD superfamily proteins 
Postdoctoral FellowWenjuan Su
Ph.D., Stony Brook UniversityPhosphoinositides and phagocytosis; PLD inhibitor  
Graduate StudentHuiyan Huang
BS, Fudan Univ.,
Shanghai, P. R. of China
Mitochondrial fusion  
Graduate StudentOladapo Yeku
BS, Medgar Evers CollegeMitochondrial fusion and disease  
Graduate StudentWahida AliB.S. SUNY BinghamtonPLD roles in phagocytosis 
Graduate Student-
mentor:
Dr. Guangwei Du
Akua Bonsra-RoachB.S. Stony Brook UniversityPIP Kinases and PA 

 

Former Lab Members:

Past TitleNameCurrent Position
TechnicianRitu GoyankaGraduate Student, NYU
 Wei AoTechnician, SUNY Stony Brook
Post-DocsOlga E. RedinaAssoc.. Prof., U. Novosibirsk, Russia
 Juan A. CrosbyPost-doc., UMDNJ, Newark, NJ
 Hilde JanssensFlyMine Administrator, England
 Guangwei DuAssistant Professor, University of Texas at Houston
 Gary Jenkins 
 Xiao Yu 
 Ping HuangInstructor, Harvard University
 Grad. StudentsWilliam C. ColleyPost-doc., St. Judes Hospital, Memphis, TN
 Tsung-Chang SungPost-doc., The Salk Institute
 Yue ZhangPost-doc., SUNY Stony Brook
 Suyong YunClinical pharmacology and discovery medicine investigator
 Si WuGraduate Student, Computer Science, SUNY Stony Brook
 Danxia KeMemorial Sloan-Kettering Cancer Center, New York, NY
  Nianzhou Xiao Medical Residency
 Margie LaLondeResident, Fast-track program in Psychiatry, Columbia University
 Seok-Yong ChoiAssistant Professor Chonam University, South Korea
 Elizabeth Scotto-LavinoPost-doc, BNL

 

Selected Publications:

Huang, H., Gao, Q. Peng, X.X., Choi, S.-Y., Sarma, K., Ren, H., Morris, A.J., and Frohman, M.A. (2011) piRNA-associated germline nuage formation and spermatogenesis require MitoPLD pro-fusogenic mitochondrial-surface lipid signaling. Developmental Cell, 20:376-387.

Huang, P., Yeku, O., Zong, H., Tsang, P., Su, W., Xu, X., Teng, S., Osisami, M., Kanaho, Y., Pessin, J.E., and Frohman, M.A. (2011) PI4P5-Kinase a deficiency alters dynamics of glucose-stimulated insulin release and protects against type 2 diabetes and obesity in mice. Diabetes,60:454-63.

Elvers et al., (2010) Impaired integrin aIIbb3 activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Science Signaling, 3:1-10.

Tsukahara et al. (2010) The novel second messenger Cyclic PA Negatively Regulates the Nuclear Hormone Receptor PPARγ. Molecular Cell, 39:421-32.

Dall’Armi, C., Hurtado-Lorenzo, A., Voronov, S.V., Yeku, O., Frohman, M.A., and Di Paolo, G. (2010) The Phospholipase D1 Pathway Modulates Macroautophagy. Nature Communications, 1:142-152.

Scotto-Lavino, E., Garcia-Diaz, M., Du, G., and Frohman, M.A. (2010) The basis for the isoform-specific interaction of Myosin Phosphatase subunits PP1c b and MYPT1. J. Biol. Chem., 285:6419-24.

Huang, H., Choi, S.-Y., and Frohman, M.A. (2010) A Quantitative Assay for Mitochondrial Fusion using Renilla Luciferase Complementation. Mitochondrion, 10:559-66.

Nishikimi et al. (2009) Sequential Regulation of DOCK2 Dynamics by Two Phospholipids during Neutrophil Chemotaxis. Science, 324:384-7.

Du, G. and Frohman, M.A. (2009) A lipid-signaled myosin phosphatase surge disperses cortical contractile force early in cell spreading. Mol. Biol. Cell, 1:200-8.

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 PLD pharmacological inhibitor that alters cell spreading and inhibits chemotaxis. Mol. Pharm. 75:437-46.

Yang, J.-S. et al. (2008) COPI vesicle fission: a role for phosphatidic acid and insight into Golgi maintenance. Nature Cell Biol., 10:1146-53.

Scotto-Lavino,E, Du,G, and Frohman,MA (2007) 5’ End cDNA Amplification using Classic RACE. Nature Protocols, 1:2555-2562.

Zhao, C., Du, G., Skowronek, K., Frohman, M.A., and Bar-Sagi, D. (2007) Phospholipase D2-generated PA couples EGFR stimulation to Ras activation by Sos. Nature Cell Biol, 9:707-12.

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 Biol., 8:1255-62.

LaLonde, M.M., Janssens, 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. 169:471-9.

Sasaki, J. et al. (2005) The phosphatidylinositol 4-phosphate 5-kinase PIPKIa is a negative regulator of anaphylaxis and FceRI signaling. J. Exp. Med., 201:859-70.

Huang, P., Altshuller, Y.M., Hou, J.C., Pessin, J.E., and Frohman, M.A. (2005) Insulin-stimulated plasma membrane fusion of the Glut4 glucose transporter is regulated by PLD1. Mol. Biol. Cell, 16:2614–23.

Du, G., Huang, P., Liang, B.T. and. Frohman, M.A. (2004) PLD2 localizes to the plasma membrane and regulates AgntII receptor endocytosis. Mol. Biol. Cell, 15:1024-30.

Du, G, Altshuller, YM, Vitale, N, Huang, P, Morris, AJ, Bader, MF, and Frohman, MA (2003) Regulation of PLD subcellular cycling through coordination of multiple membrane association motifs. J. Cell Biol 62:305-15.

Vitale, N., Caumont, A.S., Chasserot-Golaz, S., Wu, S., Zhang, Y., Morris, A.M., Frohman, M.A. and Bader, M.F (2001) PLD1: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J., 20:2424-34.

Zhang, Y, Altshuller, Y.A., Hammond, S.A., Hayes, F., Morris, A.J., and Frohman, M.A. (1999) Loss of Receptor Regulation by a PLD1 mutant unresponsive to Protein Kinase C.  EMBO J., 18:6339-6348.

Honda et al. (1999) Phosphatidylinositol 4-phosphate 5-kinasea is a Downstream Effector of the Small G Protein ARF6 in Membrane Ruffle Formation. Cell, 99:521–32.

Colley, W.C., Sung, T.-C., Roll, R., Jenco, J., Hammond, S.M., Altshuller, Y.M., Bar-Sagi, D., Morris, A.J., and Frohman, M.A. (1997) Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr. Biol. 7:191-201.

Sung et al. (1997) Mutagenesis of Phospholipase D defines a superfamily including a trans-Golgi viral protein required for poxvirus pathogenicity. EMBO J. 16:4519-4530.

Chong et al. (1995) REST:  A Mammalian Silencer Protein that Restricts Sodium Channel Gene Expression to Neurons. Cell 80:949-957.

Hammond, S.M., Altshuller, Y.M., Sung, T.-C., Rudge, S.A., Rose, K., Engebrecht, J., Morris, A.J, and Frohman, M.A. (1995) Human ARF-activated phosphatidylcholine-specific Phospholipase D Defines a New and Highly Conserved Gene Family. J. Biol. Chem. 270: 29640-43.

Frohman, M.A., Dush, M.K., and Martin, G.R. (1988). Rapid production of full-length cDNAs from rare transcripts by amplification using a single gene-specific oligonucleotide primer. PNAS 85:8998-9002.

Research queries regarding billing, ordering, and shipping should be addressed to Ms. Diane Riccardo (diriccardo@notes.cc.sunysb.edu), CMM 466, 632-1634 (phone), 632-1695 (fax).

Administrative or Personnel queries should be addressed to the Pharmacology
Department Administrator, Lynda Perdomo-Ayala (lynda@pharm.stonybrook.edu),
BST8-140, 631-444-3050 (phone).

Shipping: Frohman Lab, 495 CMM, Stony Brook University, Stony Brook, NY, 11794-5140