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Related Research Units

Gastroenterology, Hepatology and Nutrition Research
Hansen Lab Research

Research Overview

The Ras superfamily consists of more than 100 members divided into five families: Ras, Rho, Arf, Rab, and Ran. Ras-like G proteins typically function as molecular switches by cycling between an active, GTP-bound and an inactive, GDP-bound state. Ras-like G proteins rely on GTPase-activating proteins (GAPs) to promote GTP hydrolysis and guanine nucleotide exchange factors (GEFs) to facilitate the exchange of GDP for GTP. The GEFs and GAPs exert spatial and temporal control of Ras-like G protein signaling. They also serve as effector proteins, permitting cross-talk between various Ras-like G proteins. My current work focuses on a subset of Rho GEFs and GAPs and the roles that these molecules play in epithelial morphogenesis and oncogenic transformation.

First, I am interested in DOCK protein signaling. DOCK proteins are GEFs for Rac and CDC42 proteins of the Rho branch of Ras-like proteins. My lab previously demonstrated that GIT proteins, which possess GAP activity toward Arf proteins, repress Crk- and Rac-regulated motile and invasive capacities. We subsequently established that GIT proteins exert these functions by negatively regulating the activity of the RacGEF DOCK5. In ongoing work, we have determined a role for DOCK5 downstream of Ras and are actively pursuing the significance of this discovery to human cancer cells with oncogenic Ras mutations.

Second, I am interested in the p190 RhoGAPs p190A and p190B. In past work, we have established that p190A and p190B mediate pivotal cross-talk between various Rho proteins. ARHGAP35, the gene that encodes p190A, is a major cancer gene. Recently, we defined a mechanism whereby p190A acts as a tumor suppressor: p190A and its ortholog p190B repress YAP-TEAD-mediated gene transcription to promote contact inhibition of cell proliferation. Currently, we are seeking to refine our understanding of the link between p190 RhoGAP and Hippo signaling, insight that should prove useful in improving therapy for cancers with loss of p190A expression.

Research Background

Physician-scientist with a focus on cancer cell biology. Extensive experience in designing research programs, managing diverse research teams, participating in collaborative research efforts, engaging CROs, as well as communicating discoveries. Clinical oncology experience with license to practice medicine in Denmark. Expertise in translating omics-based approaches into target discovery with mechanistic understanding of gene and protein function. Highly prolific in generating custom-engineered tools, including cell models, libraries, antibodies and devices. Successful track record of attracting extramural funding and philanthropical donations. Recruited $2M endowment to Boston Children's Hospital. Pending patent on targeted oncology therapy with promise of resilience towards common resistance mechanisms.

Publications

  1. TruD technology for the study of epi- and endothelial tubes in vitro. PLoS One. 2024; 19(5):e0301099. View Abstract
  2. p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor-suppressor function mediated by p190A RhoGAP. Cell Rep. 2023 12 26; 42(12):113486. View Abstract
  3. p120 RasGAP and ZO-2 are essential for Hippo signaling and tumor suppressor function mediated by p190A RhoGAP. bioRxiv. 2023 May 23. View Abstract
  4. Mitochondrial transporter expression patterns distinguish tumor from normal tissue and identify cancer subtypes with different survival and metabolism. Sci Rep. 2022 10 11; 12(1):17035. View Abstract
  5. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells. Clin Exp Immunol. 2021 02; 203(2):304-314. View Abstract
  6. p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth. Oncogene. 2020 08; 39(33):5570-5587. View Abstract
  7. A quantitative single-cell assay for retrograde membrane traffic enables rapid detection of defects in cellular organization. Mol Biol Cell. 2020 03 19; 31(7):511-519. View Abstract
  8. INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling. Elife. 2018 10 25; 7. View Abstract
  9. Correction: p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. J Cell Biol. 2018 Sep 03; 217(9):3313. View Abstract
  10. p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. J Cell Biol. 2018 09 03; 217(9):3183-3201. View Abstract
  11. CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma. Gastroenterology. 2017 12; 153(6):1662-1673.e10. View Abstract
  12. Genome editing using FACS enrichment of nuclease-expressing cells and indel detection by amplicon analysis. Nat Protoc. 2017 03; 12(3):581-603. View Abstract
  13. The focal adhesion-associated proteins DOCK5 and GIT2 comprise a rheostat in control of epithelial invasion. Oncogene. 2017 03 30; 36(13):1816-1828. View Abstract
  14. Interferon-?-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology. 2015 Jun; 4(6):e1008824. View Abstract
  15. High-efficiency genome editing via 2A-coupled co-expression of fluorescent proteins and zinc finger nucleases or CRISPR/Cas9 nickase pairs. Nucleic Acids Res. 2014 Jun; 42(10):e84. View Abstract
  16. A ßPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis. Curr Biol. 2012 Oct 09; 22(19):1747-54. View Abstract
  17. Distinct roles of cadherin-6 and E-cadherin in tubulogenesis and lumen formation. Mol Biol Cell. 2011 Jun 15; 22(12):2031-41. View Abstract
  18. RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells. Mol Cell. 2009 Aug 28; 35(4):511-22. View Abstract
  19. The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity. J Cell Biol. 2009 May 18; 185(4):673-84. View Abstract
  20. Coordination of Rho and Rac GTPase function via p190B RhoGAP. Curr Biol. 2008 Oct 28; 18(20):1606-11. View Abstract
  21. The PIX-GIT complex: a G protein signaling cassette in control of cell shape. Semin Cell Dev Biol. 2008 Jun; 19(3):234-44. View Abstract
  22. GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. EMBO J. 2006 May 03; 25(9):1848-59. View Abstract
  23. Rnd3/RhoE induces tight junction formation in mammary epithelial tumor cells. Exp Cell Res. 2005 Apr 15; 305(1):74-82. View Abstract
  24. Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J. 2003 Aug 15; 22(16):4155-65. View Abstract
  25. Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr Biol. 2003 Jul 01; 13(13):1106-15. View Abstract
  26. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol. 2001 Sep; 3(9):831-8. View Abstract
  27. Induced expression of Rnd3 is associated with transformation of polarized epithelial cells by the Raf-MEK-extracellular signal-regulated kinase pathway. Mol Cell Biol. 2000 Dec; 20(24):9364-75. View Abstract
  28. ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. J Biol Chem. 1998 Jan 02; 273(1):23-7. View Abstract
  29. Cloning and characterization of human phosphomannomutase, a mammalian homologue of yeast SEC53. Glycobiology. 1997 Sep; 7(6):829-34. View Abstract
  30. Wortmannin, an inhibitor of phosphoinositide 3-kinase, inhibits transcytosis in polarized epithelial cells. J Biol Chem. 1995 Nov 24; 270(47):28425-32. View Abstract
  31. Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem. 1995 Jun 30; 270(26):15693-701. View Abstract
  32. Gs alpha stimulates transcytosis and apical secretion in MDCK cells through cAMP and protein kinase A. J Cell Biol. 1994 Aug; 126(3):677-87. View Abstract
  33. Endocytosis of desmosomal plaques depends on intact actin filaments and leads to a nondegradative compartment. Eur J Cell Biol. 1993 Dec; 62(2):362-71. View Abstract
  34. Molecules internalized by clathrin-independent endocytosis are delivered to endosomes containing transferrin receptors. J Cell Biol. 1993 Oct; 123(1):89-97. View Abstract
  35. Multivesicular bodies in HEp-2 cells are maturing endosomes. Eur J Cell Biol. 1993 Aug; 61(2):208-24. View Abstract
  36. Are caveolae involved in clathrin-independent endocytosis? Trends Cell Biol. 1993 Aug; 3(8):249-51. View Abstract
  37. Entry of Shiga toxin into cells. Zentralbl Bakteriol. 1993 Apr; 278(2-3):296-305. View Abstract
  38. Clathrin and HA2 adaptors: effects of potassium depletion, hypertonic medium, and cytosol acidification. J Cell Biol. 1993 Apr; 121(1):61-72. View Abstract
  39. Protein toxins: mode of action and cell entry. Biochem Soc Trans. 1992 Nov; 20(4):724-7. View Abstract
  40. Effects of brefeldin A on endocytosis, transcytosis and transport to the Golgi complex in polarized MDCK cells. J Cell Biol. 1992 Oct; 119(2):259-72. View Abstract
  41. Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum. Nature. 1992 Aug 06; 358(6386):510-2. View Abstract
  42. Internalization efficiency of the transferrin receptor. Exp Cell Res. 1992 Mar; 199(1):19-28. View Abstract
  43. Ricin transport in brefeldin A-treated cells: correlation between Golgi structure and toxic effect. J Cell Biol. 1991 Nov; 115(4):971-81. View Abstract
  44. The preendosomal compartment comprises distinct coated and noncoated endocytic vesicle populations. J Cell Biol. 1991 May; 113(4):731-41. View Abstract
  45. Localization of urokinase-type plasminogen activator receptor on U937 cells: phorbol ester PMA induces heterogeneity. Exp Cell Res. 1990 Apr; 187(2):255-62. View Abstract
  46. Endocytosis, intracellular transport and transcytosis of the toxic protein ricin by a polarized epithelium. Eur J Cell Biol. 1990 Feb; 51(1):96-109. View Abstract
  47. Internalized ricin and the plasma membrane glycoprotein MAM-6 colocalize in the trans-Golgi network of T47D human breast carcinoma cells. Exp Cell Res. 1989 Dec; 185(2):373-86. View Abstract
  48. Effect of insulin on growth and expression of smooth muscle isoactin in human breast gland myoepithelial cells in a chemically defined culture system. Eur J Cell Biol. 1989 Dec; 50(2):500-9. View Abstract
  49. Neurofilament-like pattern of reactivity in human foetal PNS and spinal cord following immunostaining with polyclonal anti-glial fibrillary acidic protein antibodies. J Neurocytol. 1989 Aug; 18(4):427-36. View Abstract

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