Photo of Malcolm Whitman,  PhD

Malcolm Whitman, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-1320


mwhitman@hms.harvard.edu

Malcolm Whitman, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Professor, Developmental Biology, Harvard School Of Dental Medicine

DF/HCC PROGRAM AFFILIATION

Research Abstract

Abstract: Our lab studies signals that regulate the specification and maintenance of cell differentiation during early embryogenesis, tissue regeneration, and disease pathogenesis. We use the frog embryo and tissue culture cells as model systems, and study primarily the regulation and action of the TGFß superfamily of ligands. Specific areas of current interest include (full description of our interests can be found at whitman.med.harvard.edu):

1) TGFß specificity in pattern regulation during embryogenesis TGFß superfamily members regulate an extraordinary variety of biological processes, including the establishment of early embryonic body pattern, the formation and patterning of tissues and organ systems in later development, and the onset of pathological processes, including fibrosis, tumor metastasis, and angiogenesis, in the adult. One of our major goals has been to understand the basis for the tissue specific regulation of transcription that occurs in response to TGFß signaling. Several years ago, we identified a transcription factor in early embryos, FAST-1, that specifically directs TGFß signal transducers, the Smads, to early embryonic promoters. We arecurrently investigating how FAST-1 and other embryo-specific transcription factors mediate patterning by TGFßs.

2) Specificity of a small molecule natural product as an inhibitor of TGFß regulated wound healing, fibrosis, and tumor development. We are studying a natural product derivative that has been shown to act as a potent regulator of fibrosis and extracellular matrix deposition in vivo, and to inhibit TGFß signaling in vitro. This small molecule acts with ~1000 fold greater potency than current “rationally designed” inhibitors of TGFß signaling, and with unexplained specificity of action towards extracellular matrix deposition, making it a promising therapeutic for wound healing, tumor metastasis, and a wide range of fibrotic diseases. We have identified the first molecular targets for this compound, and are studying how these targets mediate the specific action of this compound.

3) Role of TGFßs in complex tissue regeneration. Xenopus tadpoles can fully regenerate their tails after amputation, re-forming organized muscle, nerves, and connective tissue. We have found that TGFß signaling is essential for this process, and are currently dissecting the multiple signaling steps that regulate regeneration of complex structures.

4) TGFß superfamily regulation of muscle size and development. Muscle size is negatively regulated by the TGFß ligand myostatin. The mechanisms controlling myostatin activity in vivo are poorly understood. We are currently studying novel mechanisms by which myostatin is locally regulated in the extracellular space, providing new insights into how muscle size is controlled in health and disease.

Publications

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  • Bordoli MR, Yum J, Breitkopf SB, Thon JN, Italiano JE, Xiao J, Worby C, Wong SK, Lin G, Edenius M, Keller TL, Asara JM, Dixon JE, Yeo CY, Whitman M. A secreted tyrosine kinase acts in the extracellular environment. Cell 2014; 158:1033-44. PubMed
  • Rienhoff HY, Yeo CY, Morissette R, Khrebtukova I, Melnick J, Luo S, Leng N, Kim YJ, Schroth G, Westwick J, Vogel H, McDonnell N, Hall JG, Whitman M. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am J Med Genet A 2013; 161A:2040-6. PubMed
  • Whitman M, Rosen V, Brivanlou AH, Groppe JC, Sebald W, Mueller T. Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3. Nat Med 2013; 19:809-10. PubMed
  • Danciu TE, Whitman M. Oxidative stress drives disulfide bond formation between basic helix-loop-helix transcription factors. J Cell Biochem 2010; 109:417-24. PubMed
  • Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 2009; 324:1334-8. PubMed
  • Onuma Y,Watanabe A,Aburatani H,Asashima M,Whitman M. TRIQK, a novel family of small proteins localized to the endoplasmic reticulum membrane, is conserved across vertebrates. Zoolog Sci 2008; 25:706-13. PubMed
  • Anderson SB, Goldberg AL, Whitman M. Identification of a novel pool of extracellular pro-myostatin in skeletal muscle. J Biol Chem 2008; 283:7027-35. PubMed
  • Ho DM, Whitman M. TGF-beta signaling is required for multiple processes during Xenopus tail regeneration. Dev Biol 2008; 315:203-16. PubMed
  • Ho DM, Chan J, Bayliss P, Whitman M. Inhibitor-resistant type I receptors reveal specific requirements for TGF-beta signaling in vivo. Dev Biol 2006; 295:730-42. PubMed
  • Onuma Y, Asashima M, Whitman M. A Serpin family gene, Protease nexin-1 has an activity distinct from protease inhibition in early Xenopus embryos. Mech Dev 2006; 123:463-71. PubMed
  • Kolk SM, Whitman MC, Yun ME, Shete P, Donoghue MJ. A unique subpopulation of Tbr1-expressing deep layer neurons in the developing cerebral cortex. Mol Cell Neurosci 2006; 32:200-14. PubMed
  • Ho DM, Yeo CY, Whitman M. The role and regulation of GDF11 in Smad2 activation during tailbud formation in the Xenopus embryo. Mech Dev 2010; 127:485-95. PubMed
  • Weisberg E, Winnier GE, Chen X, Farnsworth CL, Hogan BL, Whitman M. A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is expressed during early embryogenesis. Mech Dev 1999; 79:17-27. PubMed
  • Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 1997; 389:85-9. PubMed
  • LaBonne C, Whitman M. Localization of MAP kinase activity in early Xenopus embryos: implications for endogenous FGF signaling. Dev Biol 1997; 183:9-20. PubMed
  • Chen X, Rubock MJ, Whitman M. A transcriptional partner for MAD proteins in TGF-beta signalling. Nature 1996; 383:691-6. PubMed
  • Huang HC, Murtaugh LC, Vize PD, Whitman M. Identification of a potential regulator of early transcriptional responses to mesoderm inducers in the frog embryo. EMBO J 1995; 14:5965-73. PubMed
  • LaBonne C, Burke B, Whitman M. Role of MAP kinase in mesoderm induction and axial patterning during Xenopus development. Development 1995; 121:1475-86. PubMed
  • LaBonne C, Whitman M. Mesoderm induction by activin requires FGF-mediated intracellular signals. Development 1994; 120:463-72. PubMed
  • Whitman M, Melton DA. Involvement of p21ras in Xenopus mesoderm induction. Nature 1992; 357:252-4. PubMed
  • Thomsen G, Woolf T, Whitman M, Sokol S, Vaughan J, Vale W, Melton DA. Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures. Cell 1990; 63:485-93. PubMed
  • Hall DJ, Jones SD, Kaplan DR, Whitman M, Rollins BJ, Stiles CD. Evidence for a novel signal transduction pathway activated by platelet-derived growth factor and by double-stranded RNA. Mol Cell Biol 1989; 9:1705-13. PubMed
  • Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 1988; 332:644-6. PubMed
  • Whitman M, Kaplan D, Roberts T, Cantley L. Evidence for two distinct phosphatidylinositol kinases in fibroblasts. Implications for cellular regulation. Biochem J 1987; 247:165-74. PubMed
  • Kaplan DR, Whitman M, Schaffhausen B, Pallas DC, White M, Cantley L, Roberts TM. Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell 1987; 50:1021-9. PubMed
  • Kaplan DR, Whitman M, Schaffhausen B, Raptis L, Garcea RL, Pallas D, Roberts TM, Cantley L. Phosphatidylinositol metabolism and polyoma-mediated transformation. Proc Natl Acad Sci U S A 1986; 83:3624-8. PubMed
  • Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 1985; 315:239-42. PubMed
  • Sugimoto Y, Whitman M, Cantley LC, Erikson RL. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci U S A 1984; 81:2117-21. PubMed
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