Research

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Steen Hansen, MD, PhD

Steen Hansen, PhD
Department:
Medicine Research
Division
Gastroenterology, Hepatology and Nutrition Research
Hospital Title:
Staff Scientist
Academic Title:
Assistant Professor of Pediatrics, Harvard Medical School
Contact:
617-919-4544
Contact Via Email
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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.

Publications

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  1. 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. 2016 Sep 26.
  2. 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.
  3. 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.
  4. 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 9; 22(19):1747-54.
  5. 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.
  6. 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.
  7. Frank SR, Adelstein MR, Hansen SH. GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. EMBO J. 2006 May 3; 25(9):1848-59.
  8. 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.
  9. 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.
  10. 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 1; 13(13):1106-15.
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  12. 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.
  13. 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.
  14. 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 2; 273(1):23-7.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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 6; 358(6386):510-2.
  28. Hansen SH, Sandvig K, van Deurs B. Internalization efficiency of the transferrin receptor. Exp Cell Res. 1992 Mar; 199(1):19-28.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. Wenande E, Olesen UH, Nielsen MM, Janfelt C, Hansen SH, Anderson RR, Haedersdal M. Fractional laser-assisted topical delivery leads to enhanced, accelerated and deeper cutaneous 5-fluorouracil uptake. Expert Opin Drug Deliv. 2016 Nov 28; 1-11.
  40. Wojtak R, Hansen SH, Hjorth J. Gravitational redshift of galaxies in clusters as predicted by general relativity. Nature. 2011 Sep 29; 477(7366):567-9.
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