Research Overview

We are interested in two areas:

(a) Ras and RAF are major oncogenes in human cancer. We are investigating the role of Rho-family GTP-binding proteins in oncogenic epithelial cell transformation by the Ras-activated RAF-MEK-ERK pathway. Altered Rho signaling is fundamental to acquisition of motile and proliferative capacities in cancer. Ras and RAF induce expression of Rnd3 and activation of Rac1, which both are members of the Rho-family. We established that Rnd proteins and Rac1 modulate signaling by p190 RhoGAP. In collaboration with Morten Frödin (BRIC), we moreover determined that Ras and RAF, through the effector kinase p90RSK, control expression of numerous genes that confer motile and invasive capacities through activation of Rac1. We are continuing efforts to further define Rac and Rho signaling pathways downstream of Ras and RAF.

(b) The PAK-PIX-GIT complex is important in epithelial morphogenesis and oncogenic transformation. Class I PAKs are Cdc42/Rac effector molecules that bind directly to PIX proteins, which serve as activators of Cdc42/Rac. In turn, PIX proteins form stable complexes with GIT molecules, putative inactivators of the Arf family of GTP-binding proteins. We first demonstrated that PAK and PIX shuttle between focal adhesions and adherens junctions to regulate contact inhibition. Subsequently, we established that class I PAKs, PIX, and GIT proteins control pivotal processes in epithelial cells, including acquisition of invasive properties and protection from apoptosis. At the molecular level, one would expect that the PAK-PIX-GIT complex mediates cross talk between Arf- and Rho-family G proteins to regulate the activity of class I PAKs. Yet, despite our studies and those of others, defining the molecular mechanisms underlying the diverse properties of class I PAKs, PIX and GIT proteins remains a major ongoing challenge.

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  1. Hendel KK, Bagger C, Olesen UH, Janfelt C, Hansen SH, Haedersdal M, Lerche CM. Fractional laser-assisted topical delivery of bleomycin quantified by LC-MS and visualized by MALDI mass spectrometry imaging. Drug Deliv. 2019 Dec; 26(1):244-251. View abstract
  2. Henriksen M, Alkjær T, Raffalt PC, Jørgensen L, Bartholdy C, Hansen SH, Bliddal H. Opioid-Induced Reductions in Gait Variability in Healthy Volunteers and Individuals with Knee Osteoarthritis. Pain Med. 2019 Jan 12. View abstract
  3. Luong P, Hedl M, Yan J, Zuo T, Fu TM, Jiang X, Thiagarajah JR, Hansen SH, Lesser CF, Wu H, Abraham C, Lencer WI. INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling. Elife. 2018 10 25; 7. View abstract
  4. Frank SR, Köllmann CP, Luong P, Galli GG, Zou L, Bernards A, Getz G, Calogero RA, Frödin M, Hansen SH. Correction: p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. J Cell Biol. 2018 Sep 03; 217(9):3313. View abstract
  5. Frank SR, Köllmann CP, Luong P, Galli GG, Zou L, Bernards A, Getz G, Calogero RA, Frödin M, Hansen SH. p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. J Cell Biol. 2018 Sep 03; 217(9):3183-3201. View abstract
  6. Engelholm LH, Riaz A, Serra D, Dagnæs-Hansen F, Johansen JV, Santoni-Rugiu E, Hansen SH, Niola F, Frödin M. 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
  7. Lonowski LA, Narimatsu Y, Riaz A, Delay CE, Yang Z, Niola F, Duda K, Ober EA, Clausen H, Wandall HH, Hansen SH, Bennett EP, Frödin M. 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
  8. Frank SR, Köllmann CP, van Lidth de Jeude JF, Thiagarajah JR, Engelholm LH, Frödin M, Hansen SH. 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
  9. Bellucci R, Martin A, Bommarito D, Wang K, Hansen SH, Freeman GJ, Ritz J. 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
  10. Duda K, Lonowski LA, Kofoed-Nielsen M, Ibarra A, Delay CM, Kang Q, Yang Z, Pruett-Miller SM, Bennett EP, Wandall HH, Davis GD, Hansen SH, Frödin M. 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
  11. Frank SR, Bell JH, Frödin M, Hansen SH. A ßPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis. Curr Biol. 2012 Oct 09; 22(19):1747-54. View abstract
  12. Jia L, Liu F, Hansen SH, Ter Beest MB, Zegers MM. 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
  13. Doehn U, Hauge C, Frank SR, Jensen CJ, Duda K, Nielsen JV, Cohen MS, Johansen JV, Winther BR, Lund LR, Winther O, Taunton J, Hansen SH, Frödin M. 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
  14. Tzaban S, Massol RH, Yen E, Hamman W, Frank SR, Lapierre LA, Hansen SH, Goldenring JR, Blumberg RS, Lencer WI. 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
  15. Bustos RI, Forget MA, Settleman JE, Hansen SH. Coordination of Rho and Rac GTPase function via p190B RhoGAP. Curr Biol. 2008 Oct 28; 18(20):1606-11. View abstract
  16. Frank SR, Hansen SH. 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
  17. Frank SR, Adelstein MR, Hansen SH. 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
  18. Rubenstein NM, Chan JF, Kim JY, Hansen SH, Firestone GL. Rnd3/RhoE induces tight junction formation in mammary epithelial tumor cells. Exp Cell Res. 2005 Apr 15; 305(1):74-82. View abstract
  19. Zegers MM, Forget MA, Chernoff J, Mostov KE, ter Beest MB, Hansen SH. Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J. 2003 Aug 15; 22(16):4155-65. View abstract
  20. Wennerberg K, Forget MA, Ellerbroek SM, Arthur WT, Burridge K, Settleman J, Der CJ, Hansen SH. Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr Biol. 2003 Jul 01; 13(13):1106-15. View abstract
  21. O'Brien LE, Jou TS, Pollack AL, Zhang Q, Hansen SH, Yurchenco P, Mostov KE. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol. 2001 Sep; 3(9):831-8. View abstract
  22. Hansen SH, Zegers MM, Woodrow M, Rodriguez-Viciana P, Chardin P, Mostov KE, McMahon M. 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
  23. Frank S, Upender S, Hansen SH, Casanova JE. ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. J Biol Chem. 1998 Jan 02; 273(1):23-7. View abstract
  24. Hansen SH, Frank SR, Casanova JE. Cloning and characterization of human phosphomannomutase, a mammalian homologue of yeast SEC53. Glycobiology. 1997 Sep; 7(6):829-34. View abstract
  25. Hansen SH, Olsson A, Casanova JE. 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
  26. Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen SH, Nishimoto I, Lisanti MP. Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem. 1995 Jun 30; 270(26):15693-701. View abstract
  27. Hansen SH, Casanova JE. 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
  28. Holm PK, Hansen SH, Sandvig K, van Deurs B. 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
  29. Hansen SH, Sandvig K, van Deurs B. Molecules internalized by clathrin-independent endocytosis are delivered to endosomes containing transferrin receptors. J Cell Biol. 1993 Oct; 123(1):89-97. View abstract
  30. van Deurs B, Holm PK, Sandvig K, Hansen SH. Are caveolae involved in clathrin-independent endocytosis? Trends Cell Biol. 1993 Aug; 3(8):249-51. View abstract
  31. van Deurs B, Holm PK, Kayser L, Sandvig K, Hansen SH. Multivesicular bodies in HEp-2 cells are maturing endosomes. Eur J Cell Biol. 1993 Aug; 61(2):208-24. View abstract
  32. Hansen SH, Sandvig K, van Deurs B. Clathrin and HA2 adaptors: effects of potassium depletion, hypertonic medium, and cytosol acidification. J Cell Biol. 1993 Apr; 121(1):61-72. View abstract
  33. Sandvig K, Dubinina E, Garred O, Prydz K, Kozlov JV, Hansen SH, Van Deurs B. Entry of Shiga toxin into cells. Zentralbl Bakteriol. 1993 Apr; 278(2-3):296-305. View abstract
  34. Sandvig K, Dubinina E, Garred O, Prydz K, Kozlov JV, Hansen SH, van Deurs B. Protein toxins: mode of action and cell entry. Biochem Soc Trans. 1992 Nov; 20(4):724-7. View abstract
  35. Prydz K, Hansen SH, Sandvig K, van Deurs B. 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
  36. Sandvig K, Garred O, Prydz K, Kozlov JV, Hansen SH, van Deurs B. Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum. Nature. 1992 Aug 06; 358(6386):510-2. View abstract
  37. Hansen SH, Sandvig K, van Deurs B. Internalization efficiency of the transferrin receptor. Exp Cell Res. 1992 Mar; 199(1):19-28. View abstract
  38. Sandvig K, Prydz K, Hansen SH, van Deurs B. 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
  39. Hansen SH, Sandvig K, van Deurs B. The preendosomal compartment comprises distinct coated and noncoated endocytic vesicle populations. J Cell Biol. 1991 May; 113(4):731-41. View abstract
  40. Hansen SH, Behrendt N, Danø K, Kristensen P. 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
  41. van Deurs B, Hansen SH, Petersen OW, Melby EL, Sandvig K. 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
  42. Petersen OW, Hansen SH, Laursen I, van Deurs B. 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
  43. Hansen SH, Petersen OW, Sandvig K, Olsnes S, van Deurs B. 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
  44. Hansen SH, Stagaard M, Møllgård K. 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