M. Falk , Ph.D.
Dept. of Biological Sciences
111 Research Drive
Iacocca Hall, #D218
(610) 758-4004 fax
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Microscopic photographs taken by Lehigh’s Matthias
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Membrane Protein Biosynthesis, Structure & Function
of Gap Junctions and other Cell-Cell Junctions, Microscopy
Cells of multi-cellular organisms are autonomous units, yet constantly
depend on signals from their surrounding. Signals can either be
transmitted between cells and the extra-cellular milieu, or directly
from cell to cell. Information exchange is mediated by membrane
proteins that assemble into localized, spatial and temporal organized
multiunit transmembrane protein complexes, such as tight junctions,
adherens junctions, desmosomes, focal adhesions, hemi-desmosomes,
chemical synapses, immunological synapses, and gap junctions. We
are interested in understanding how such complex signaling structures
are biosynthesized, how they are structured, and how their function
Gap junctions are the only known cellular structures that allow
a direct transfer of signaling molecules from cell-to-cell by forming
hydrophilic channels that bridge the opposing plasma membranes of
neighboring cells. The crucial role of gap junction mediated intercellular
communication (GJIC) for coordination of development, tissue function,
and cell-homeostasis is now well documented; and mutations in gap
junction channel protein encoding genes can result in a number of
diseases, that include deafness, cataracts, severe dermatological
disorders, and cancer. In addition, recent findings indicate that
GJIC also plays a significant role in transient cell-cell contacts,
and that gap junction hemi-channels (connexons) by themselves can
function in intra/extra-cellular signaling.
Biosynthesis of these channels is a complicated, highly regulated
process. Over the past decade we have studied where and how the
gap junction channel proteins (connexins) are synthesized, elucidated
gap junction channel subunit compatibility, characterized signals
that regulate subunit interaction, determined cellular components
involved in these processes, characterized how newly synthesized
gap junction channels are trafficked to the plasma membrane, and
have investigated how gap junctions are assembled.
Our research plan is based on an integrated approach that combines
novel high resolution and live-cell imaging techniques with molecular
biology, biochemistry, immunological, and functional assays. Proteins
are analyzed in cell-free expression systems, in tissues, and especially
in cultured living cells. Four aspects of gap junction structure
and function are of current interest: (1) The characterization of
molecular signals that regulate composition of gap junctions and
gap junction channels. (2) To investigate the degradation process
of gap junctions and what role this process might have for the direct
spread of viral pathogens between cells. (3) To investigate the
cause of human disorders that correlate with point mutations in
a and b connexins; and (4) to characterize other cellular components
and their role in gap junction assembly and function.
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Wang, S., Kowal, T.J., Marei, M.K, Falk, M.M., and Jain, H. 2013. Nanoporosity significantly enhances the biological performance of engineered glass scaffolds. Tissue Engineering Part A (in press)
Thévenin, A.F. Kowal, T.J., Fong, J.T., Kells, R.M., Fisher, C.G., and Falk, M.M. 2013. Proteins and mechanisms regulating gap junction assembly, internalization and degradation. Physiology 28:93-116.
Baker, S.M, and Falk, M.M. 2012. Natural inflammatory mediators thrombin and endothelin modulate gap junction intercellular communication and cell-cell adhesion. eBook. Nova Science Publishers, Inc., Hauppauge, NY, USA (ISBN: 978-1-62417-375-2).
Falk, M.M., Fong, J.T., Kells, R.M., O'Laughlin, M.C., Kowal, T.J., Thévenin, A.F. 2012. Degradation of endocytosed gap junctions by autophagosomal and endo-/lysosomal pathways: a perspective. J. Membr. Biol. 245:465-76.
Fong, J.T., Kells, R.M., Gumpert, A.M., Marzillier, J.Y., Davidson, M.W. and Falk, M.M. 2012. Internalized gap junctions are degraded by autophagy. Autophagy 8:794-811. (Evaluated by ‘Faculty of 1000’)
Baker, S.M., and Falk, M.M. 2012. Chapter 18: Thrombin-mediated regulation of gap junction intercellular communication and cell-to-cell adhesion, pp. 247-254. In Thrombin: Function and Pathophysiology, Th. Stief (Ed.), Nova Science Publishers, Inc., Hauppauge, NY, USA (ISBN: 978-1-61942-087-8).
Jain, R.H., Marzillier, J.Y., Kowal, T.J., Wang, S., Jain, H., and Falk, M.M. 2011. Expression of mineralized tissue-associated proteins is highly upregulated in MC3T3-E1 osteoblasts grown on a borosilicate glass substrate. Advances in Bioceramics and Porous Ceramics IV: Ceramic Engineering & Science Proceedings, R. Narayan & P. Colombo (Eds.) vol. 32 (6):111-122.
Wang, S., Falk, M.M., Rashad, A., Saad, M.M., Marques, A.C., Almeida, R.M., Marei, M.K., and Jain, H. 2011. Evaluation of 3D nano-macro porous bioactive glass scaffold for hard tissue engineering. J. Mater. Sci: Mater. Med. 22:1195-1203.
Govindarajan, R., Chakraborty, S., Johnson, K.E., Falk, M.M., Wheelock, M.J., Johnson, K.R., and Mehta, P.P. 2010. Assembly of connexin43 into gap junctions is regulated differentially by E-cadherin and N-cadherin in rat liver epithelial cells. Mol. Biol. Cell 21:4089-4107.
Vueva, Y., Gama, A., Almeida, R., Wang S., Jain, H., and Falk, M.M. 2010. Monolithic glass scaffolds with dual porosity prepared by polymer-induced phase separation and sol-gel. J. Americ. Ceramic Soc. 93(7):1945-1949.
Falk, M.M. 2010. Adherens junctions remain dynamic. BMC Biology 8:34-37.
Baker, S.M., R.W. Buckheit III, and Falk, M.M. 2010. Green-to-red photoconvertible fluorescent proteins: tracking cell and protein dynamics on standard wide-field mercury arc-based microscopes. BMC Cell Biology 11:15-24. (Evaluated by ‘Faculty of 1000’) (highly accessed)
Chakraborty, S., S. Mitra, M.M. Falk, S. Caplan, M.J. Wheelock, K.R. Johnson; and P.M. Mehta. 2010. E-Cadherin Differentially Regulates the Assembly of Connexin43 and Connexin32 into Gap Junctions in Human Squamous Carcinoma Cells. J. Biol. Chem. 285:10761-10776.
Jain, R.H., Wang, S., Moawad, H., Falk, M.M., Jain, H. 2010. Glass Bone Implants: The Effect of Surface Topology on Attachment and Proliferation of Osteoblast Cells on 45S Bioactive Glass. In Engineering Biomaterials for Regenerative Medicine; S. Bhatia, S. Bryant, J.A. Burdick, J.M. Karp, K. Walline (Eds.). Mater. Res. Soc. Symp. Proc. Vol. 1235, Warrendale, PA, 1235-RR03-47 (6 pages).
Marques, A., Almaida, R., Thima, A., Falk, M.M., Jain, H. 2009. Sol-gel derived glass scaffold with high pore interconnectivity and enhanced bioactivity. J. Materials Res., 24:3495-3502.
Moawad, H.M., Wang, S., Jain, H., Falk, M.M. 2009. Effect of zinc on bioactivity of nano-macroporous soda-lime phosphofluorosilicate glass-ceramics. Ceramic Engineering & Science Proceedings, Vol. 30, Issue 6, pp. 179-190.
Falk, M.M. S. Baker, A.M. Gumpert, D. Segretain, and R.W. Buckheit III. 2009. Gap junction turnover is achieved by the internalization of small endocytic double-membrane vesicles. Mol. Biol. Cell 20:3342-3352. (Evaluated by ‘Faculty of 1000’)
Gilleron, J., C. Fiorini, D. Carette, C. Avondet, M.M. Falk, D. Segretain, and G. Pointis. 2008. Molecular reorganization of Cx43, ZO-1, and c-Src interactions during HCH-induced internalization of gap junctions. J. Cell Sci. 121:4069-4078.
Baker, S.M., N. Kim, D. Segretain, and M.M. Falk. 2008. Acute internalization of gap junctions in vascular endothelial cells in response to inflammatory mediator-induced G-protein coupled receptor activation. FEBS Lett. 582:4039-4046 (Including Journal Issue Cover).
Gumpert, A.M., J.S. Varco, S.M. Baker, M. Piehl, and M.M. Falk. 2008. Double-membrane gap junction internalization requires the clathrin-mediated endocytic machinery. FEBS Lett. 582, 2887-2892.
Iovine, M.K., A.M. Gumpert, M.M. Falk, and T.C. Mendelsohn. 2008. Cx23, a connexin with only four extracellular-loop cysteines, forms functional gap junction channels and hemichannels. FEBS Lett. 582:165-170.
Gilleron, J., D., Segretain, and M.M. Falk. 2007. Gap junction trafficking and regulation. Reactome: a curated knowledgebase of biological pathways. Cold Spring Harbor Laboratory, European Bioinformatics Institute, and GO Consortium.http://www.reactome.org
Piehl, M., C. Lehmann, A. Gumpert, J.-P. Denizot, D. Segretain, and M.M. Falk. 2007. Internalization of large double-membrane intercellular vesicles by a clathrin-dependent endocytic process. Mol. Biol. Cell 18:337-347. (Evaluated by ‘Faculty of 1000’)
Eastman, S. D., T. H. Chen, M. M. Falk, T. C. Mendelson, and M. K. Iovine. 2006. Phylogenetic analysis of three complete gap junction gene families reveals lineage-specific duplications and highly supported gene classes. Genomics. 2006 Feb; 87(2):265-74.
Segretain, D, and M.M. Falk, 2004. Regulation of connexin
biosynthesis, assembly, gap junction formation, and removal. Biochim.
Biophys. Acta 1662, 3-21.
Lagrée, V., K. Brunschwig, P. Lopez, N. B. Gilula, G. Richard,
and M.M. Falk. 2003. Specific amino acid residues
in the N-terminus and TM3 implicated in channel function and oligomerization
compatibility of connexin43. J. Cell Science 116, 3189-3201.
Falk, M. M. 2002. Genetic tags for labelling live
cells: gap junctions and beyond. Trends Cell Biol. 12:399-404.
Lauf, U., B.N.G. Giepmans, P. Lopez, S. Braconnot, S.-C. Chen, and
M.M. Falk. 2002. Dynamic trafficking and delivery
of connexons to the plasma membrane and accretion to gap junctions
in living cells. Proc. Natl. Acad Sci. USA 99:10446-10451.
(On-Line Movies at: http://www.pnas.org/cgi/content/full/162055899/DC1)
Falk, M. M. 2001. Connexins/Connexons: Cell-free
expression. Methods Mol. Biol. 154:91-116.
Giepmans, B.N.G., I. Verlaan, T. Hengeveld, M.M. Falk, and W.H.
Moolenaar. 2001. Gap junction protein connexin-43
interacts directly with microtubules. Current Biol. 11:1364-1368.
Lauf, U., P. Lopez, and M.M. Falk. 2001. Expression
of fluorescently tagged connexins: a novel approach to rescue function
of oligomeric DsRed-tagged proteins. FEBS Lett. 498:11-15.
Falk, M.M. and U. Lauf. 2001. High-resolution fluorescence
deconvolution microscopy and tagging with the autofluorescent tracers
CFP, GFP, and YFP to study the structural composition of gap junctions
in living cells. Microsc. Res. Tech. 52:251-262.
M. M. 2000. Cell-free synthesis for analyzing the membrane integration,
oligomerization, and assembly characteristics of gap junction connexins. Methods 20:165-179.
Falk, M.M. 2000. Connexin-specific distribution
within gap junctions revealed in living cells. J. Cell Sci. 113:4109-4120.
(On-Line Movies at: http://jcs.biologists.org/cgi/content/full/113/22/4109/DC1)
Falk, M.M. 2000. Biosynthesis and structural composition
of gap junction intercellular membrane channels. Eur. J. Cell
M. M. and N. B. Gilula. 1998. Connexin membrane
protein biosynthesis is influenced by polypeptide positioning
within the translocon and signal peptidase access. J. Biol.
T.W., R.N. Beachy, and M.M. Falk. 1997. Cell-free expression of a GFP fusion
protein allows quantitation in vitro and in vivo. Current Biol. 7:R207-R208.
Falk, M.M., L.K. Buehler, N.M. Kumar, and N.B. Gilula. 1997.
Cell-free Synthesis and Assembly of Connexins into Functional Gap
Junction Membrane Channels. EMBO J. 16:2703-2716.
Falk, M.M., N.M. Kumar, and N.B. Gilula. 1994.
Membrane Insertion of Gap Junction Connexins: Polytopic Channel
Forming Membrane Proteins. J. Cell Biol. 127:343-355.
|| Assistant Professor, Department of Biological Sciences,
Lehigh University, Bethlehem, Pennsylvania, USA
||Assistant Professor, Department of Cell Biology,
The Scripps Research Institute, La Jolla, California, USA
||Senior Research Associate, Department of Cell Biology,
The Scripps Research Institute, La Jolla, California, USA
||Postdoctoral Fellow, Department of Cell Biology,
The Scripps Research Institute, La Jolla, California, USA
Sponsor: Dr. Norton B. Gilula
Project title: Structure and function of gap junction membrane
||Ph.D. Defense, Curriculum in Molecular Biology, Cell Biology,
Virology, and Biochemistry, University of Heidelberg, Heidelberg,
||Ph.D. thesis, Center for Molecular Biology (ZMBH),
University of Heidelberg, Heidelberg, Germany
Thesis Advisor: Dr. E. Beck; chair: Dr. H. Schaller
Thesis project: Structure and function of foot-and-mouth disease
virus (Picornaviridae) proteins
||Diploma in Biology (M.A.), University of Giessen, Giessen,
||Diploma thesis, Department of human virology,
University of Giessen, Giessen, Germany
Thesis Advisor: Dr. H. Niemann, chair: Dr. H. Bauer
Thesis project: Characterization of Golgi retention signals
in the E1 transmembrane glycoprotein of MHV (Coronaviridae)
||Vor-Diplom in Biology (B.A.), University of Giessen, Giessen,
||Studied Biology at the University of Giessen, Giessen, Germany
The web-site of the Falk-Lab at the “Scripps Research Institute,
La Jolla, CA (TSRI):
Falk-Lab Research Report 2002:
Falk-Lab Research Report 2001:
Falk-Lab Research Report 2000:
Falk-Lab Research Report 1999:
Falk-Lab Research Report 1998:
Falk-BioS 368 (Cell Biology lab) Fall 2005 syllabus