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Bretscher, Anthony Paul
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advisory group member
Research
research overview
- We are interested in the functional organization and regulation of microfilaments in eucaryotic cells. Microfilaments, which are composed of actin filaments and associated proteins, are involved in a host of functions, including the determination of cellular shape and providing the machinery for a variety of motile processes. We are using diverse biochemical, structural, genetic and cell biological approaches to investigate the general principles underlying microfilament structure and function in eucaryotic cells. Two major projects are underway. The first is a detailed investigation into the molecular organization of the microfilaments that make up the cytoskeleton of microvilli present on intestinal epithelial cells. In this work we are purifying and characterizing the various microfilament-associated proteins (including villin, fimbrin, brush border myosin I, and ezrin) and, together with ultrastructural studies, are piecing together the precise function of each component. We then explore whether related proteins perform similar functions in other, less easily studied, microfilament arrangements. Current studies suggest that ezrin performs a central role in coordinating cell structure with membrane traffick in the apical aspect of epithelial cells. The second major project exploits the yeast Saccharomyces cerevisiae for a combined biochemical and genetic approach to the structure and function of a microfilament in this simple eucaryote. We are presently identifying, purifying and characterizing microfilament-associated proteins related to those under study in higher eucaryotic cells. Over the last few years, we have shown that one major component of the yeast actin cytoskeleton, namely the polarized actin cables that run from the bud into the mother cell, are polarized highways for the delivery of secretory vesicles for cell growth, as well as providing the underlying polarity for organelle segregation during the cell cycle. Working with the actin cables is a myosin-V molecular motor that carries cargoes along the cables to their destination. Our goal is to understand at the molecular level how cables are established, and how they are used by the myosin-V to deliver their cargo, both of which have to be regulated in a cell cycle-dependent manner.
principal investigator on
- MICROFILAMENT ORGANIZATION AND REGULATION awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2012 - 2015
- MICROFILAMENTS IN THE YEAST SACCHAROMYCES CEREVISIAE awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2011 - 2015
- THE ROLE OF MMRIP IN CARGO DELIVERY BY MYO2P awarded by NATL INST OF GENERAL MEDICAL SCIENCES, NIH 2011 - 2013
area(s) of concentration/expertise
keywords
- cell biology
- cell polarity
- cell signaling
- cellular organization
- membrane trafficking
- microfilaments
submitted impact statement
Publications
individual publications
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academic article
- EPI64 interacts with Slp1/JFC1 to coordinate Rab8a and Arf6 membrane trafficking. Molecular and Cellular Biology. 23:701-715. 2012
- Local cycles of LOK/SLK-dependent phosphorylation restrict ezrin function to the apical aspect of epithelial cells.. Journal of Cell Biology. 199:969-984. 2012
- Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells.. Journal of Cell Biology. 199:969-984. 2012
- Myosin-V is activated by binding secretory cargo and released in coordination with Rab/exocyst function. Developmental Cell. 23:769-781. 2012
- PDZ interactions regulate rapid turnover of the scaffolding protein EBP50 in microvilli. Journal of Cell Biology. 198:195-203. 2012
- The Tumor Suppressor Merlin Controls Growth in Its Open State, and Phosphorylation Converts It to a Less-Active More-Closed State.. Developmental Cell. 22:703-705. 2012
- Yeast formin Bni1p has multiple localization regions that function in polarized growth and spindle orientation. Molecular Biology of the Cell. 23:412-422. 2012
- Yeast formin Bni1p has multiple localization regions that function in polarized growth and spindle orientation.. Molecular Biology of the Cell. 23:412-422. 2012
- Z-line formins promote contractile lattice growth and maintenance in striated muscles of C. elegans. Journal of Cell Biology. 198:87-102. 2012
- Membrane-trafficking sorting hubs: cooperation between PI4P and small GTPases at the trans-Golgi Network. Trends in Cell Biology. 21:515-525. 2011
- PI4P and Rab inputs collaborate in Myosin-V-dependent transport of secretory compartments in yeast. Developmental Cell. 20:47-59. 2011
- The UBX Protein SAKS1 negatively regulates Endoplasmic Reticulum-Associated Degradation and p97-dependent degragation. Journal of Biological Chemistry. 286:4892-4901. 2011
- A regulated complex of the scaffolding proteins PDZK1 and EBP50 with ezrin contribute to microvillar organization. Molecular Biology of the Cell. 21:1519-29. 2010
- Organizing the cell cortex: the role of ERM proteins. Nature Reviews Molecular Cell Biology. 11:276-87. 2010
- The scaffolding protein EBP50 regulates microvillar assembly in a phosphorylation-dependent manner. Journal of Cell Biology. 191:397-413. 2010
- The yeast formin Bnr1p has two localization regions that show spatially and temporally distinct association with septin structures. Molecular Biology of the Cell. 21:1253-62. 2010
- Epithelial polarity: dual Lkb1 pathways regulate apical microvilli. Developmental Cell. 16:491-2. 2009
- Polarized growth in budding yeast in the absence of a localized formin. Molecular Biology of the Cell. 20:2540-8. 2009
- T cell antigen receptor signaling and immunological synapse stability require myosin IIA. Nature Immunology. 10:531-9. 2009
- The scaffold protein PDZK1 undergoes a head-to-tail intramolecular association that negatively regulates its interaction with EBP50. Biochemistry. 48:2261-71. 2009
- Analysis of unregulated formin activity reveals how yeast can balance F-actin between different microfilament-based organizations . Molecular Biology of the Cell. 19:1474-1484. 2008
- A Zn finger/FH2 domain containing protein FOZI-1 acts redundantly with CeMyoD to specify striated body wall muscle fates in the C. elegans postembryonic mesoderm. Development. 134:19-29. 2007
- Expression of the Cytoskeleton Linker Protein Ezrin in Human Cancers. Clinical & Experimental Metastasis. 134:19-29. 2007
- Immune synapse formation requires ZAP-70 recruitment by ezrin and CD43 removal by moesin. Journal of Cell Biology. 179:733-746. 2007
- EPI64 regulates microvillar sub-domains and structure. Journal of Cell Biology. 175:803-813. 2006
- Regulated phosphorylation of budding yeast's essential myosin V heavy chain, Myo2p. Molecular Biology of the Cell. 17:1812-1821. 2006
- Self-masking in an intact ERM-merlin protein: an active role for the central a-helical domain. Journal of Molecular Biology. 117:1547-1552. 2006
- Ezrin mutants affecting dimerization and activation. Biochemistry. 44:3926-3932. 2005
- Microtubule tips redirect actin assembly. Developmental Cell. 8:458-459. 2005
- Cellular retinaldehyde-binding protein interacts with ERM-binding phosphoprotein 50 in retinal pigment epithelium. Investigative Ophthalmology and Visual Science. 45:393-401. 2004
- Global mapping of the yeast genetic interaction network. Science. 303:808-13. 2004
- Inhibition and Redistribution of NHE3, the Apical Na+/H+ Exchanger, by Clostridium difficile Toxin B. Journal of General Physiology. 123:491-504. 2004
- Mechanisms of polarized growth and organelle segregation in yeast. Annual Review of Cell and Developmental Biology. 20:559-591. 2004
- Stable and dynamic axes of polarity utilize distinct forming isoforms in budding yeast. Molecular Biology of the Cell. 15:4971-4989. 2004
- The EBP50-moesin interaction: structural analysis of a binding site regulated by direct masking on the FERM domain. Journal of Cell Science. 117:1547-1552. 2004
- Microtubule asymmetry. Science. 300:2040-2041. 2003
- Polarized growth and organelle segregation in yeast - the tracks, motors, and receptors. Journal of Cell Biology. 160:811-816. 2003
- Structure of the active FERM Domain of Ezrin: conformational and mobility changes identify keystone interactions. Journal of Biological Chemistry. 278:4949-4956. 2003
- Two Rho pathways converge to regulate formin-dependent actin assembly in yeast. Journal of Cell Biology. 161:1081-1092. 2003
- Distinct cell type expression of EBP50 and E3KARP: EBP50 is generally expressed with ezrin in specific epithelia, whereas E3KARP is not. Europ. J. Cell Biol.. 81:61-68. 2002
- ERM proteins and merlin: integrators at the cell cortex. Nature Reviews: Molecular and Cell Biology. 3:586-599. 2002
- Formins direct Arp2/3-independent actin filament assembly to polarize cell growth in yeast. Nature Cell Biology. 4:32-41. 2002
- Insight into the molecular mechanism of pathogen durability and epidemics: Group A Streptococcus inhibitor of complement diminishes bacterial adherence to human epithelial cells. Proceedings of the National Academy of Sciences of the United States of America. 99:7646-7651. 2002
- Microfilaments and microtubules: the news from yeast. Current Opinion in Microbiology. 5:564-574. 2002
- Role of formins in actin assembly: nucleation and barbed end association. Science. 297:612-615. 2002
- Secretory vesicle transport velocity in living cells depends on the myosin-V lever-arm length. Journal of Cell Biology. 156:35-39. 2002
- Heirachy of N- and C-ERMAD associations and common ligands between ezrin and merlin. Journal of Biological Chemistry. 276:7621-7629. 2001
- Identification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP. Journal of Cell Biology. 153:191-206. 2001
- Identification of two distinct structural motifs that when added to the C-terminal tail of the rat LH receptor redirect the internalized hormone receptor complex from a degradation to a recycling pathway. Molecular Endocrinology. 15:1624-1635. 2001
- Immunoblot detection of antigens in immunoprecipitates. BioTechniques. 31:1-2. 2001
- Nodes of Ranvier form in association with ERM-positive Schwann cell processes. Proceedings of the National Academy of Sciences of the United States of America. 98:1235-1240. 2001
- Ras regulates the polarity of the yeast actin cytoskeleton through the stress response pathway. Molecular Biology of the Cell. 12:1541-1555. 2001
- ERM-merlin and EBP50 protein families in plasma membrane organization and function. Ann. Rev. Cell & Devel. Biol.. 16:113-143. 2000
- Identification of a novel member of the chloride intracellular channel gene family (CLIC5) that Associates with the actin cytoskeleton of Placental Microvilli. Molecular Biology of the Cell. 11:1509-1521. 2000
- Myosin V orientates the mitotic spindle in yeast. Nature. 406:1013-1015. 2000
- Myosin V orients the mitotic spindle in yeast. Nature. 406:1013-1016. 2000
- Polarization of Cell Growth in Yeast. I. Establishment and Maintenance of Polarity States. J. Cell Sci.. 113:365-375. 2000
- Polarization of Cell Growth in Yeast. II. The role of the cortical actin cytoskeleton. J. Cell Sci.. 113:571-585. 2000
- Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin-binding tail domain. Cell. 101:259-270. 2000
- The cytoskeleton: from regulation to function. EMBO Reports. 1:473-476. 2000
- A kinase regulatable PDZ interaction controls endocytic sorting of the ß-2-adrenergic receptor. Nature. 401:286-290. 1999
- Dynamic association of moesin with the membrane skeleton of thrombin activated platelets. Blood. 93:2128-9. 1999
- Moesin, the major ERM protein of lymphocytes and platelets, differs from ezrin in its insensitivity to calpain. FEBS Lett. 443:31-36. 1999
- Regulation of cortical structure by the ezrin-radixin-moesin protein family. Current Opinions In Cell Biology. 11:109-116. 1999
- The carboxyl-terminal domain of a yeast myosin V has a direct role in secretory vesicle targeting. Journal of Cell Biology. 147:791-807. 1999
- The cytoskeletal linker protein moesin: decreased levels in Wiskott-Aldrich syndrome platelets and identification of a cleavage pathway in normal platelets. Brit. J. Haematology. 106:216-223. 1999
- An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton. Journal of Biological Chemistry. 273:19797-19801. 1998
- C-Terminal Threonine Phosphorylation Activates ERM Proteins to Link the Cell's Cortical Lipid Bilayer to the Cytoskeleton. Biochem Biophys Res Commun. 253:561-5. 1998
- Differential expression of moesin in the intestinal brush border of hibernating ground squirrels. Cryobiology. 37:146-154. 1998
- The carboxy-terminal region of EBP50 binds to a site in the amino-terminal domain of ezrin that is masked in the dormant monomer. Journal of Biological Chemistry. 273:18378-18384. 1998
- Tropomyosin-containing actin cables direct the Myo2p-dependent polarized delivery of secretory vesicles in budding yeast. Journal of Cell Biology. 143:1931-1945. 1998
- Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures. J. Cell Sci.. 110:3011-3018. 1997
- Identification of EBP50: a PDZ domain containing phosphoprotein that associates with members of the ERM family. Journal of Cell Biology. 139:169-179. 1997
- Mutations synthetically lethal with tpm1∆ lie in genes involved in morphogenesis. Genetics. 147:1595-1607. 1997
- A rho-GAP, encoded by BEM2, regulates microfilaments in yeast. Molecular Biology of the Cell. 6:1011-1024. 1995
- Ezrin from placenta exists as stable monomers and elongated dimers. Biochemistry. 34:16830-16837. 1995
- Ezrin oligomers are major cytoskeletal components of placental microvilli: their possible involvement in cortical morphogenesis. Journal of Cell Biology. 131:1231-1242. 1995
- Ezrin self-association involves binding of an N-terminal domain to a normally masked C-terminal domain that includes the F-actin binding site. Molecular Biology of the Cell. 6:1061-1075. 1995
- Parallel secretory pathways to the cell surface in yeast. Journal of Cell Biology. 131:297-310. 1995
- Tropomyosin is essential in yeast, yet the TPM1 and TPM2 products perform distinct functions. Journal of Cell Biology. 128:383-392. 1995
- Brush border myosin-I microinjected into cultured cells is targeted to actin-containing surface structures. J. Cell Sci.. 107:1623-1631. 1994
- What are the basic functions of microfilaments? Insights from studies in budding yeast. Journal of Cell Biology. 126:821-826. 1994
- Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells, whereas moesin is found primarily in endothelial cells. J. Cell Sci.. 105:1025-1043. 1993
- Heterotypic and homotypic associations between ezrin and moesin, two putative membrane-cytoskeletal linking proteins. Proceedings of the National Academy of Sciences of the United States of America. 90:10846-10850. 1993
- Microfilaments and Membranes. Current Opinion in Cell Biology. 5:653-660. 1993
- Moesin, like ezrin, colocalizes with actin in the cortical cytoskeleton, but its expression is more variable. J. Cell Sci.. 105:219-232. 1993
- Characterization of TPM1 disrupted yeast cells indicates an involvement of tropomyosin in directed vesicular transport. Journal of Cell Biology. 118:285-299. 1992
- Construction of a GAL1 -regulated yeast cDNA expression library and its application to the identification of genes whose overexpression causes lethality in yeast. Genetics. 132:665-673. 1992
- Identification and molecular characterization of a calmodulin-binding subunit gene (CMP1) of protein phosphatase 2B from Saccharomyces cerevisiae; an a-factor inducible gene. Europ. J. Biochem.. 204:713-723. 1992
- Identification of ezrin as an 81kD tyrosine phosphorylated protein in T cells. J. Immunology. 149:1847-1852. 1992
- Yeast actin is relatively well behaved. Europ. J. Biochem.. 206:949-955. 1992
- Microfilament structure and function in the cortical cytoskeleton. Ann. Rev. Cell Biol.. 7:337-374. 1991
- Molecular aspects of microfilament structure and assembly. Current Opinion in Structural Biology. 1:281-287. 1991
- The secretion-stimulated 80K phosphoprotein of parietal cells is ezrin, and has the properties of a membrane cytoskeletal linker in the induced apical microvilli. EMBO Journal. 10:2363-2373. 1991
- Mapping of the microvillar 110K-calmodulin complex (brush border myosin I). Identification of fragments containing the catalytic and F-actin binding sites and demonstration of a calcium-ion-dependent conformational change. Biochemistry. 29:11089-11094. 1990
- Microinjection of villin into cultured cells results in rapid and long-lasting changes in cell morphology, but does not interfere with cytokinesis, cell motility or membrane ruffling. Journal of Cell Biology. 111:2475-2485. 1990
- Disruption of the single tropomyosin gene in yeast leads to a disappearance of actin cables from the cytoskeleton. Cell. 57:233-242. 1989
- Landmark mapping: a general method for localizing cysteine residues in a protein. Proceedings of the National Academy of Sciences of the United States of America. 86:3549-3553. 1989
- Preliminary biochemical characterization of the stereocilia and cuticular plate of hair cells of the chick cochlea. Journal of Cell Biology. 109:1711-1724. 1989
- Preparation of immobilized monomeric actin and its use in the isolation of protease- and ribonuclease-free pancreatic deoxyribonuclease I. Europ. J. Biochem.. 179:215-219. 1989
- Purification of tropomyosin from Saccharomyces cerevisiae and identification of related proteins in Schizosaccharomyces and Physarum. Proceedings of the National Academy of Sciences of the United States of America. 86:90-93. 1989
- Rapid phosphorylation and reorganization of ezrin and spectrin accompany morphological changes in A-431 cells induced by EGF. Journal of Cell Biology. 108:921-930. 1989
- Reassociation of microvillar core proteins: making a microvillar core in vitro. Journal of Cell Biology. 108:495-502. 1989
- The calmodulin and F-actin binding domain of caldesmon lies in the carboxyl terminal domain whereas the molecular weight heterogeneity lies in the middle of the molecule. Journal of Biological Chemistry. 264:2869-2875. 1989
- cDNA cloning and sequencing of the protein-tyrosine kinase substrate, ezrin, reveals homology to band 4.1. EMBO Journal. 8:4133-4142. 1989
- Mapping of the microvillar 110K-calmodulin complex: Calmodulin-associated or -free fragments of the 110 kd polypeptide bind F-actin and retain ATPase activity. Journal of Cell Biology. 106:367-373. 1988
- ATPase activity of the microvillar 110K-calmodulin complex is activated in Mg2+ and inhibited in K+EDTA by F-actin. FEBS Lett.. 225:269-272. 1987
- Calcium-regulated cooperative binding of the microvillar 110K-calmodulin complex to F-actin: Formation of decorated filaments. Journal of Cell Biology. 105:325-333. 1987
- Smooth muscle caldesmon is a long flexible monomeric protein in solution that can readily undergo reversible intra- and inter-molecular sulfhydryl cross-linking: A mechanism for caldesmon's F-actin bundling activity. Journal of Biological Chemistry. 262:7429-7437. 1987
- F-actin aggregates in transformed cells contain fimbrin and α-actinin but apparently lack tropomyosin. Europ. J. Cell Biol.. 39:313-320. 1986
- Fodrin is part of the detergent resistant cytoskeleton before and after cytochalasin treatment. European J. Cell Biol.. 39:321-327. 1986
- The protein-tyrosine kinase substrate, p81, is homologous to a chicken microvillar core protein. Journal of Cell Biology. 102:660-669. 1986
- Thin filament regulatory proteins of smooth- and non-muscle cells. Nature (Lond.). 321:726-727. 1986
- Identification and localization of immunoreactive forms of caldesmon in smooth and non-muscle cells: a comparison with the distributions of tropomyosin and α-actinin. Journal of Cell Biology. 100:1656-1663. 1985
- Microvillus 110K-calmodulin: effects of nucleotides on isolated cytoskeletons and the interaction of the purified complex with F-actin. Journal of Cell Biology. 100:1455-1465. 1985
- Surveying the Cytoskeleton. Review of Cell and Muscle Motility vol. 6. Cell. 43:563-564. 1985
- Smooth muscle caldesmon: rapid purification and F-actin cross-linking properties. Journal of Biological Chemistry. 259:12873-12880. 1984
- Induced morphological changes in isolated microvilli: regulation of membrane topology in vitro by submembranous microfilaments. Europ. J. Cell Bio.. 29:187-192. 1983
- Purification of an 80,000 dalton protein that is a component of the isolated microvillus cytoskeleton, and its localization in non-muscle cells. Journal of Cell Biology. 97:425-432. 1983
- Characterization and ultrastructural role of the major components of the intestinal microvillus cytoskeleton. Cold Spring Harbor. Symp. Quant. Biol.. 46:871-879. 1982
- Immunolocalization of several cytoskeletal proteins in inner ear sensory and supporting cells. Hearing Research. 6:75-89. 1982
- Fimbrin is a cytoskeletal protein that cross-links F-actin in vitro. Proceedings of the National Academy of Sciences of the United States of America. 78:6849-6853. 1981
- Villin associates with specific microfilaments structures as seen by immunofluorescence microscopy on tissue sections and cells microinjected with villin. Experimental Cell Research. 135:213-219. 1981
- Calcium control of the intestinal microvillus cytoskeleton: its implications for the regulation of microfilament organizations. Proceedings of the National Academy of Sciences of the United States of America. 77:6458-6482. 1980
- Fimbrin: a new microfilament-associated protein present in microvilli and other cell surface structures. Journal of Cell Biology. 86:335-340. 1980
- Plasma membranes from intestinal microvilli and erythrocytes contain cytochromes b5 and P-420. Biochimica et Biophysica Acta. 600:739-755. 1980
- Villin is a major protein of the microvillus cytoskeleton which binds both G- and F-actin in a calcium dependent manner. Cell. 20:839-847. 1980
- Alpha-actinins from chicken skeletal muscle and smooth muslce show considerable chemical and immunological differences. European Journal of Biochemistry. 100:237-243. 1979
- Villin: the major microfilament-associated protein of the intestinal microvillus. Proceedings of the National Academy of Sciences of the United States of America. 76:2321-2325. 1979
- Localization of actin and microfilament-associated proteins in the microvilli and terminal web of the intestinal brush border by immunofluorescence microscopy. Journal of Cell Biology. 79:839-845. 1978
- Nutrition of Myxococcus xanthus, a fruiting Myxobacterium. Journal of Bacteriology. 133:763-768. 1978
- Synergism between morphogenetic mutants of Myxococcus xanthus. Developmental Biology. 64:284-296. 1978
- Tropomyosin from bovine brain contains two polypeptides of slightly different molecular weights. FEBS Letters. 85:145-148. 1978
- Divergent transcription of the argECBH cluster of Escherichia coli K-12. Mutations which alter the control of enzyme synthesis. Journal of Molecular Biology. 102:205-220. 1976
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article
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book
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booksection
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conference paper
- The molecular structure of the microvillar cytoskeleton. Ion gradient-coupled transport. 13-21. 1986
- The molecular architecture of the microvillus cytoskeleton. Ciba Foundation Symp. No. 95 'Brush Border Membranes'. 1983
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past news release
- Purification of caldesmon 1986
- Purification of the intestinal microvillus cytoskeletal proteins villin, fimbrin and ezrin 1986
featured in archived article
- Bretscher named associate director of new Cornell Institute for Cell and Molecular Biology
- New Institute of Cell and Molecular Biology will raise stature of cell biology on Cornell campus
- Researchers ID molecular link key for cell growth
- Weill Hall, life science research center for ideas and collaboration, is open for business
Teaching
Service
service to the profession
- American Association for the Advancement of Science Member 1982 -
- American Society for Cell Biology Member 1980 -
- ASCB Image Library Member 2004 - 2006
- ASCB Council Member 2003 - 2005
- Search Committee for Editor-in-chief of Molecular Biology of the Cell Committee Chair - 2004
- Special Symposium Committee, ASCB Chairperson - 2002
Background
education and training
- M.A. in, University of Cambridge 1974
- Ph.D. in Bacterial Genetics, University of Leeds 1974
- B.A. in Experimental Physics, University of Cambridge 1971
awards and honors
Other
research keyword
- cell biology
- cell polarity
- cell signaling
- cellular organization
- membrane trafficking
- microfilaments