Mitchell Goldfarb

Mitchell Goldfarb

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Specialization
Regulation of Voltage-gated Sodium Channels by FHF Proteins

Dr. Mitchell Goldfarb is a professor in the Department of Biological Sciences.

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Education

  • BS, 1974, Massachusetts Institute of Technology
  • PhD, 1979, Massachusetts Institute of Technology

Courses

  • BIOL 370: Physiology of Nervous System (undergraduate at Hunter College)
  • BIOL 471.45: Molecular Basis of Brain & Heart Disorders (undergraduate at Hunter College)
  • BIOL 710: Molecular Biology (graduate at Hunter College)
  • BIO 72301: Neuroscience Core I (graduate at CUNY Graduate Center)

Research

FGF Homologous Factors: Regulators of Sodium Channels Controlling Brain and Cardiac Function

We have discovered and studied proteins called fibroblast growth factor homologous factors (FHFs). FHF gene mutations engineered in mice or occurring naturally in humans are associated with a range of neurological disorders. FHFs were discovered by virtue of their sequence homology to fibroblast growth factors (FGFs). While FGFs exert pleiotropic biological effects through interactions with their cell surface FGF receptors, we have demonstrated that FHFs are intracellular and bind to specific neuronal protein targets. A principal set of targets are the alpha subunits for voltage-gated sodium channels.  Using FHF knockout mice, we have shown that FHFs are required for neurons to fire robustly, and this is accomplished by FHF modulation of sodium channel fast inactivation (Goldfarb et al., 2007).  We have also shown that some FHFs induce a rapid onset long-term inactivation of sodium channels, which is mediated by an inactivation particle in the effector N-terminus of these FHF isoforms (Dover et al., 2010).  Long-term inactivation progressively slows the firing rate of neurons, a process called accommodation or frequency adaptation (Venkatesan et al., 2014).  Some of these studies have entailed the use of fast voltage-sensitive dyes, leading to the discovery that axonal spike conduction occurs in an FHF-independent manner (Dover et al., 2016). We have also shown mechanistically how FHF dysfunction can lead to severe epilepsies (Siekierska et al., 2016; Fry et al., 2021, Veliskova et al., 2021), stress-induced cardiac arrhythmias (Park et al., 2016; Park et al., 2020), and loss of heat nociception (Marra et al., 2023).

All Publications

  1. Goldfarb, M. (2024) Fibroblast growth factor homologous factors: Canonical and noncanonical mechanisms of action. J Physiology 602, 4097-4110 .
  2. Marra, C., Hartke, T., Ringkamp, M., Goldfarb, M. (2023) Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception. Pain 164, 1321-1331.
  3. Santucci, J., Park, D.S., Shekhar, A., Lin, X., Bu, L., Yamaguchi, N., Mintz, S., Chang, E.W., Khodadi-Jamayran, A., Redel-Traub, G., Goldfarb, M., Fishman, G.I. (2022) Contrasting ionic mechanisms of impaired conduction in FHF1- and FHF-2 deficient hearts. Circulation: Arrhythmia and Electrophysiology 15, e011296.
  4. Veliskova, J., Marra, C., Liu, Y., Shekhar, A., Park, D.S., Iatckova, V., Xie, Y., Fishman, G.I., Velisek, L., Goldfarb, M. (2021) Early-onset epilepsy and SUDEP with cardiac arrhythmia in mice carrying the EIEE47 gain-of-function Fhf1(Fgf12) missense mutation. Epilepsia 62, 1546-1558.
  5. Fry, A.E., Marra, C., 18 others, Goldfarb, M., Chung, S.-K. (2021) Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked infantile onset developmental and epileptic encephalopathy. Am. J. Hum. Genet. 108, 176-185.
  6. Park, D.S., Shekhar, A., Santucci, J., Redel-Traub, G., Solinas, S.M.G., Mintz, S., Lin, X., Chang, E.W., Narke, D., Xia, Y., Goldfarb, M., Fishman, G.I. (2020) Ionic mechanisms of impulse propagation failure in the FHF2-deficient heart. Circ. Res. 127, 1536-1548.
  7. Soda, T., Mapelli, L., Locatelli, F., Botta, L., Goldfarb, M., Prestori, F., D'Angelo, E.M. (2019) Hyperexcitability and hyperplasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism. J. Neurosci. 39, 2383-2397.
  8. Nandi, S., Gutin, G., Blackwood, C., Kamatkar, M., Lee, K., Fishell, Gl, Wang, F., Goldfarb, M., Hebert, J.M. (2017) FGF-dependent, context-driven role for FRS adapters in the early telencephalon. J. Neurosci. 37, 5690-5698.
  9. Park, D., Shekhar, A., Marra, C., Lin X., Vasquez, C., Solinas, S., Kelley, K., Morley, G., Goldfarb, M., Fishman, G.I. (2016) Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nature Commun. 7, 12966.
  10. Dover, K., Marra, C., Solinas, S., Popovic, M., Subramaniyam, S., Zecevic, D., D'Angelo, E., Goldfarb, M. (2016) FHF-independent conduction of action potentials along the leak-resistant cerebellar granule cell axon. Nature Commun. 7, 12895
  11. Siekierska, A., Isrie, M., Liu, Y., Scheldeman, C., Vanthill, N., Lagae, L., de Witte, P.A.M., Van Esch, H., Goldfarb, M., Buyse, G. (2016) Gain-of-function FHF missense mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology 86, 2162-2170.
  12. Venkatesan, K., Liu, Y., Goldfarb, M. (2014) Fast-onset long-term open-state block of sodium channels by A-type FHF mediates classical spike accommodation in hippocampal pyramidal neurons. J. Neurosci. 34, 16126-16139.
  13. Goldfarb, M. (2012) Voltage gated sodium channel associated proteins and alternative mechanisms of inactivation and block. Cell. Molec. Life Sci. 69, 1067-1076.
  14. Dover, K., Solinas, S., D’Angelo, E., and Goldfarb, M. (2010) Long-term inactivation particle for voltage-gated sodium channels. J. Physiology (London) 588, 2695-2711.
  15. Giza, J., Urbanski, M.J., Prestori, F., Bandhyopadhyay, B., Yam, A., Friedrich, V., Kelley, K., D’Angelo, E. and Goldfarb, M. (2010) Behavioral and cerebellar transmission deficits in mice lacking the autism-linked gene islet brain-2. J. Neurosci. 30, 14805-14816.
  16. Diwakar, S., Magistretti, J., Goldfarb, M., Naldi, G., and D’Angelo, E. (2009) Axonal sodium channels ensure fast spike activation and back-propagation in cerebellar granule cells. J. Neurophysiol. 101, 519-532.
  17. Goetz, R., Dover, K., Laezza, F., Shtraizent, N., Huang, X., Tchetchik, D., Eliseenkova, A.V., Xu, C.-F., Neubert, T.A., Ornitz, D.M., Goldfarb, M., Mohammadi, M. (2009) Crystal structure of FHF2 unveils a conserved binding site on FHFs for the C-terminal domain of voltage-gated sodium channels. J.Biol. Chem. 284,17883-17896.
  18. Goldfarb, M. (2008) “Real Cancer Genes”, pgs 175-179. In “Life Illuminated”, Cold Spring Harbor Press; J. Witkowski, A Gann, J. Sambrook, Eds.
  19. Goldfarb, M., Schoorlemmer, J., Williams, A., Diwakar, S., Wang, Q., Huang, X., Giza, J., Tchetchik, D., Kelley, K., Vega, A., Matthews, G., Rossi, P., Ornitz, D.M., D’Angelo, E. (2007) FHFs control neuronal excitability through modulation of voltage gated sodium channels. Neuron 55, 449-463.
  20. Goldfarb, M. (2005) Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Rev. 16, 215-220.
  21. Wittmack, E.K., Rush, A.M., Craner, M.J., Goldfarb, M., Waxman, S.G. and Dib-Hajj, S. (2004) Association of FHF2B and voltage-gated sodium channel Nav1.6 in vitro and in vivo: functional implications. J. Neurosci. 24:6765-6775.
  22. Olsen, S., Garbi, M., Zampieri, N., Eliseenkova, A.N., Ornitz, D.M., Goldfarb, M. and Mohammadi, M. (2003) FHFs share structural but not functional homology to FGFs. J. Biol. Chem. 278, 34226-34236.
  23. Schoorlemmer, J. and Goldfarb, M. (2002) FGF homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase. J. Biol. Chem. 277, 49111-49119.
  24. Yan, K.S., Kuti, M., Yan, S., Farooq, A., Goldfarb, M.P., and Zhou, M.-M. (2002) FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. J. Biol. Chem. 277, 17088-17094.
  25. Goldfarb, M. (2001) Signaling by fibroblast growth factors: the inside story. Science’s STKE 106/pe38.
  26. Schoorlemmer, J. and Goldfarb, M. (2001) Fibroblast growth factor homologous factors are intracellular signalling proteins. Curr. Biol. 11, 793-797.
  27. Xu, H. and Goldfarb, M. (2001) Multiple effector domains within SNT-1 coordinate ERK activation and neuronal differentiation of PC12 cells. J. Biol. Chem. 276, 13049-13056.
  28. Hama, J., Xu, H., Goldfarb, M., and Weinstein, D.C. (2001) SNT-1/FRS2alpha physically interacts with Laloo and mediates mesoderm induction by fibroblast growth factor. Mech. Dev. 109, 195-204.
  29. Dhalluin, C., Yan, K., Plotnikova, O., Lee, K.W., Zeng, L., Kuti, M., Mujtaba, S., Goldfarb, M., and Zhou, M.-M. (2000) Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. Mol. Cell 6, 921-929. 59. Jung, J., Zheng, M., Goldfarb, M., and Zaret, K. (1999) Inititation of mammalian liver development from endoderm by fibroblast growth factors. Science 284, 1998-2003.
  30. Colvin, J.S., Feldman, B., Nadeau, J.H., Goldfarb, M., and Ornitz, D.M. (1999) Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene. Dev. Dyn. 216, 72-88.
  31. Xu, H., Lee, K.W., and Goldfarb, M. (1998) (Communication) Novel recognition motif on FGF receptor mediates direct association and activation of SNT adaptor proteins. J.Biol. Chem. 273, 17987-17990.
  32. Hartung, H., Feldman, B., Lovec, H., Coulier, F., Birnbaum, D., and Goldfarb, M. (1997) Murine FGF-12 and FGF-13: expression in embryonic nervous system, connective tissue and heart. Mech. Dev. 64(1,2), 31-39.
  33. Shrivastava, A, Radziejewski, C., Campbell, E., Kovac, L., McGlynn, M., Ryan, T.E., Davis, S., Goldfarb, M.P., Lemke, G., and Yancopoulos, G.D. (1997) An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell 1, 25-34.
  34. Lovec, H., Hartung, H., Verdier, A.S., Mattei, M.G., Birnbaum, D., Goldfarb, M., and Coulier, F. (1997) Assignment of FGF13 to human chromosome band Xq21 by in situ hybridization. Cytogenet. Cell Genet. 76, 183-184.
  35. Hartung, H., Lovec, H., Verdier, A.S., Mattei, M.G., Coulier, F., Goldfarb, M., and Birnbaum, D. (1997) Assignment of Fgf12 to mouse chromosome bands 16B1->B3 by in situ hybridization. Cytogenet. Cell Genet. 76, 185-186.
  36. Wang, J.K. and Goldfarb, M. (1997) Amino acid residues which distinguish the mitogenic potentials of two FGF receptors. Oncogene 14, 1767-1778.
  37. Verdier, A.S., Mattei, M.G., Lovec, H., Hartung, H., Goldfarb, M., Birnbaum, D., and Coulier, F. (1997) Chromosomal mapping of two novel human FGF genes, FGF11 and FGF12. Genomics 40, 151-154.
  38. Coulier, F., Pontarotti, P., Roubin, R., Hartung, H., Goldfarb, M., and Birnbaum, D. (1997) Of worms and men: An evolutionary perspective on the fibroblast growth factor (FGF) and FGF receptor families. J. Mol. Evol. 44, 43-56.
  39. Ornitz, D.M., Xu, J., Colvin, J.S., McEwen, D.G., MacArthur, C.A., Coulier, F., Gao, G., and Goldfarb, M. (1996) Receptor specificity of the fibroblast growth factor family. J. Biol. Chem. 271, 15292-15297.
  40. Wang, J.-K., Xu, H., Li, H.-C., and Goldfarb, M. (1996) Broadly expressed SNT-like proteins link FGF receptor stimulation to activators of the Ras pathway. Oncogene 13, 721-729.
  41. Valenzuela, D.M., Rojas, E., Griffiths, J.A., Compton, D.L., Gisser, M., Ip, N.Y., Goldfarb, M., and Yancoupolos, G.D. (1996) Identification of full-length and truncated forms of EHK-3, a novel member of the EPH receptor tyrosinel kinase family. Oncogene 10, 1573-1580.
  42. Gao, G. and Goldfarb, M. (1995) Heparin can activate a receptor tyrosine kinase. EMBO J. 14, 2183-2190.
  43. Stitt, T.N., 15 others, Long, G.L., Basilico, C., Goldfarb, M., Lemke, G., Glass, D.J., and Yancopoulos, G.D. (1995) The anticoagulation factor Protein S and its relative Gas6 are ligands for the Tyro3/Axl family of receptor tyrosine kinases. Cell 80, 661-670.
  44. Feldman, B., Poueymirou, W., Papaioannou, V., DeChiara, T., and Goldfarb, M. (1995) Requirement of FGF-4 for post-implantation mouse development. Science 267, 246-249.
  45. Davis, S.D., Gale, N., Aldrich, T., Maisonpierre, P., Lhotak, V., Pawson, T., Goldfarb, M., and Yancopoulos, G.D. (1994) A family of surface-bound ligands for EPH-related receptors that require clustering for activity as soluble factors. Science 266, 816-819.
  46. Hantzopoulos, P.A., Suri, C., Glass, D.J., Goldfarb, M.P., and Yancopoulos, G.D. (1994) Neuron 13, 187-201.
  47. Wang, J.-K, Gao, G., and Goldfarb, M. (1994) Fibroblast growth factor receptors have different signaling and mitogenic potentials. Mol. Cell. Biol. 14, 181-188.
  48. Conover, J.C., Ip, N.Y., Poueymirou, W.T., Bates, B., Goldfarb, M.P., DeChiara, T.M., and Yancopoulos, G.D. (1993) Ciliary neurotrophic factor maintains pluripotentiality of murine embryonic stem cells. Development 119, 559-565.
  49. Maisonpierre, P., Goldfarb, M., Yancopoulos, G.D., and Gao, G. (1993) Distinct rat genes with related profiles of expression define a TIE receptor tyrosine kinase family. Oncogene 8, 1631-1637.
  50. Zerlin, M., Julius, M.S., and Goldfarb, M. (1993) NEP - a novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. Oncogene 10, 2731-2739.
  51. Clements, D.A., Wang, J.K., Dionne, C.A., and Goldfarb, M. (1993) Activation of fibroblast growth factor (FGF) receptors by recombinant human FGF-5. Oncogene 8, 1311-1316.
  52. Drucker, B.J., and Goldfarb, M. (1993) Murine FGF-4 gene expression is spatially restricted within embryonic skeletal muscle and other tissues. Mech. Dev. 40, 155-163.
  53. Hughes, R.A., Sendtner, M., Goldfarb, M., Lindholm, D., and Thoenen, H. (1993) Evidence that fibroblast growth factor-5 is a major muscle-derived survival factor for cultured spinal motoneurons. Neuron 10, 369-377.
  54. Werner, S., Roth, W.K., Bates, B., Goldfarb, M., and Hofschneider, P.H. Fibroblast growth factor 5 protooncogene is expressed in human fibroblasts and induced by serum growth factors. (1991) Oncogene 6, 2137-2144.
  55. Glass, D.J., Nye, S.H., Hantzopoulos, P., Macchi, M.J., Squinto, S.P. Goldfarb, M., and Yancopoulos, G.D. (1991) TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low-affinity NGF receptor. Cell 66, 405-413.
  56. Haub, O. and Goldfarb, M. (1991) Expression of the fibroblast growth factor 5 gene in the mouse embryo. Development 112, 397-406.
  57. Bates, B., Hardin, J., Zhan, X., Drickamer, K. and Goldfarb, M. (1991) Biosynthesis of human fibroblast growth factor-5. Mol. Cell. Biol. 11, 1840-1845.
  58. Goldfarb, M., Deed, R., MacAllan, D., Walther, W., Dickson, C., and Peters. G. (1991) Cell transformation by INT-2 - A member of the fibroblast growth factor family. Oncogene 6, 65-71.
  59. Goldfarb, M. (1990) The fibroblast growth factor family. Cell Growth Differ. 1, 439-445.
  60. Haub, O., Drucker, B.J., and Goldfarb, M. (1990) Expression of the murine fibroblast growth factor-5 gene in the adult central nervous system. Proc. Natl. Acad. Sci. USA 87, 8022-8026.
  61. Hebert, J.M., Basilico, C., Goldfarb, M., Haub, O., and Martin, G.R. (1990) Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis. Dev. Biol. 138, 454-463.
  62. Theillet, C., Leroy, X., DeLapeyriere, O., Grosgeorges, J., Adnane, J., Raynaud, S.D., Simonlafontaine, J., Goldfarb, M., Escot, C., Birnbaum, D., and Gaudray, P. (1989) Amplification of FGF-related genes in human tumors - Possible involvement of HST in human breast carcinomas. Oncogene 4, 915-922.
  63. Rees-Jones, R.W., Goldfarb, M., and Goff, S.P. (1989) Abelson murine leukemia virus induces platelet-derived growth factor-independent fibroblast growth: correlation with kinase activity and dissociation from full morphological transformation. Mol. Cell. Biol. 9, 278-287.
  64. Nguyen, C., Roux, D., Mattei, M.G., de Lapeyriere, O., Goldfarb, M., Birnbaum, D., and Jordan, B.R. (1988) The FGF-related oncogenes hst and int-2, and the bcl-1 locus are located within one megabase in band q13 of chromosome 11, while the fgf-5 oncogene maps to 4q21. Oncogene 3, 703-708.
  65. Zhan, X., Bates, B., Hu, X., and Goldfarb, M. (1988) The FGF-5 oncogene encodes a novel protein related to fibroblast growth factors. Mol. Cell. Biol. 8, 3487-3495.
  66. Cavalieri, F., and Goldfarb, M. (1988) N-myc protooncogene expression can induce DNA synthesis in Balb/c 3T3 fibroblasts. Oncogene 2, 289-291.
  67. Zhan, X., Culpepper, A., Reddy, M., Loveless, J., and Goldfarb, M. (1987) Human oncogenes detected by a defined medium culture assay. Oncogene 1, 369-376.
  68. Cavalieri, F., and Goldfarb, M. (1987) Growth factor-deprived Balb/c 3T3 murine fibroblasts can enter the S phase following induction of c-myc gene expression. Mol. Cell. Biol. 7, 3554-3560.
  69. Zhan, X. and Goldfarb, M.P. (1986) Growth factor requirements of oncogene-transformed NIH and Balb/c 3T3 cells cultured in defined media.. Mol. Cell. Biol. 6, 3541-3544.
  70. Yancopoulos, G.D., Nisen, P.D., Tesfaye, A., Kohl, N.E., Goldfarb, M.P., and Alt, F.W. (1985) N-myc can cooperate with ras to transform normal cells in culture. Proc. Natl. Acad. Sci. USA 82, 5455-5459.
  71. Gross M, Sweet RW, Sathe G, Yokoyama S, Fasano O, Goldfarb M, Wigler M, Rosenberg M. (1985) Purification and characterization of human H-ras proteins expressed in E. coli. Mol. Cell. Biol. 10, 515-524.
  72. Kataoka T, Powers S, Cameron S, Fasano O, Goldfarb M, Broach J, Wigler M. (1985) Functional homology of mammalian and yeast RAS proteins. Cell 40, 19-26.
  73. Powers S, Kataoka T, Fasano O, Goldfarb M, Strathern J, Broach J, Wigler M. (1984) Genes in S. cerevisae encoding proteins with domains homologous to the mammalian ras proteins. Cell 36, 607-612.
  74. Barker D, McCoy, M, Weinberg R, Goldfarb M, Wigler M, Burt R, Gardner E, White R. (1983) A test of the role of two oncogenes in inherited predisposition to colon cancer. Mol. Biol. Med. 1, 199-206.
  75. Taparowsky E, Shimizu K, Goldfarb M, Wigler M. (1983) Structure and activation of the human N-ras gene. Cell 34, 581-586.
  76. Shimizu K, Birnbaum D, Ruley MA, Fasano O, Suard Y, Edlund L, Taparowsky E, Goldfarb M, Wigler M. (1983) Structure of the Ki-Ras gene of the human lung carcinoma cell line Calu-1. Nature 304, 497-500.
  77. Shimizu K, Goldfarb M, Suard Y, Perucho M, Li Y, Kamata T, Feramisco J, Stavnezer E, Fogh J, Wigler MH. (1983) Three human transforming genes are related to the viral ras oncogenes. Proc. Natl. Acad. Sci. USA 80, 2112-2116.
  78. Fasano O, Taparowsky E, Fiddes J, Wigler M, Goldfarb M. (1983) Sequence and structure of the coding region of the human H-ras-1 gene from the T24 bladder carcinoma cell line. J. Mol. Appl. Genet. 2, 173-180.
  79. Shimizu K, Goldfarb M, Perucho M, Wigler M. (1983) Isolation and preliminary characterization of the transforming gene from a human neuroblastoma cell line. Proc. Nat. Acad. Sci. USA 80, 383-387.
  80. Taparowsky, E., Suard, Y., Fasano, O., Shimizu, K., Goldfarb, M. and Wigler, M. (1982) Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300, 762-765.
  81. Goldfarb, M., Shimizu, K., Perucho, M. and Wigler, M. (1982) Isolation and preliminary characterization of a human transforming gene from T24 bladder carcinoma cells. Nature 296, 404-409.
  82. Perucho, M., Goldfarb, M.P., Shimizu, K., Lama, C., Fogh, J. and Wigler, M.H. (1981) Human tumor-derived cell lines contain common and different transforming genes. Cell 27, 467-476.
  83. Goldfarb, M.P. and Weinberg, R. A. (1981) Generation of novel, biologically active Harvey sarcoma viruses via apparent illegitamate recombination. J. Virol. 38, 136-150.
  84. Goldfarb, M.P. and Weinberg, R.A. (1981) Structure of the provirus within NIH3T3 cells transfected with the Harvey sarcoma virus DNA. J. Virol. 38, 125-135
  85. Shih, C., Shilo, B.-A., Goldfarb, M.P., Dannenberg, A. and Weinberg, R.A. (1979) Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin. Proc. Natl. Acad. Sci. USA 76, 5714-5718.
  86. Goldfarb, M.P. and Weinberg, R.A. (1979) Physical map of biologically active Harvey sarcoma virus unintegrated viral DNA. J. Virol. 32, 30-39.
  87. Andersson, P., Goldfarb, M.P. and Weinberg, R.A. (1979) A defined subgenomic fragment of in vitro synthesized Moloney sarcoma virus DNA can induce cell transformation upon transfection. Cell 16, 63-75.

Contact Details

Mitchell Goldfarb

Biological Sciences
68th Street North 810
(212) 772-5289
goldfarb@genectr.hunter.cuny.edu