Karl Tryggvason Group

Professor

Karl Tryggvason

Phone: 08-524 877 20
E-mail: Karl.Tryggvason@ki.se

Karl Tryggvason's profile page.

Karl Tryggvason´s group carries out research on the molecular structure, biology and diseases of basement membranes.

The basement membranes (BM) are specialized extracellular structures that promote cellular differentiation, migration and adhesion, and they are involved in many diseases. The group has characterized numerous BM proteins and their genes, and elucidated the molecular basis of five genetic BM diseases; Alport syndrome, diffuse leiomyomatosis, junctional epidermolysis bullosa, congenital muscular dystrophy and congenital nephrotic syndrome.

BMs are an important component of the kidney filter that is currently a major target of the group's research. The involvement of BMs in diabetes complications and tumor invasion and metastasis is also a major research focus. Furthermore, the group has carried out extensive work on matrix metalloproteinases (MMPs) and novel bacteria binding macrophage receptors MARCO and SCARA5.

 

Research projects

 

Basement Membranes involment in cancer and in stem cell differentiation

Characterization of the structure and function of BM proteins has been a central focus of the group. Type IV collagen and laminin are the main structural proteins that also have other important functions. Other important components include proteoglycans and nidogen. The group has characterized and cloned all six alpha chains of type IV collagen, nine out of eleven known laminin chains, as well as perlecan the main BM proteoglycan. Many of these proteins were first described by the group. Gene targeting in mice has been used to elucidate the biological roles of laminins and perlecan. The gamma-2 chain of the epithelium specific laminin-5 was found by the group and shown to be a remarkable marker for early detection of invasive cancers, in addition to being mutated in the skin blistering disease epidermolysis bullosa. Antibodies against laminin-5 are being tested for in vivo inhibition of cancer cell migration and dissemination. Different isoforms of trimeric laminins have been produced as recombinant proteins, and they have successfully been used in different culture conditions and differentiation of embryonic stem cells.

Selected publications

Complete primary structure of the alpha 1-chain of human basement membrane (type IV) collagen.
Soininen R, Haka-Risku T, Prockop D, Tryggvason K
FEBS Lett. 1987 Dec;225(1-2):188-94

Extensive structural differences between genes for the alpha 1 and alpha 2 chains of type IV collagen despite conservation of coding sequences.
Hostikka S, Tryggvason K
FEBS Lett. 1987 Nov;224(2):297-305

Nucleotide sequence coding for the human type IV collagen alpha 2 chain cDNA reveals extensive homology with the NC-1 domain of alpha 1 (IV) but not with the collagenous domain or 3'-untranslated region.
Hostikka S, Kurkinen M, Tryggvason K
FEBS Lett. 1987 Jun;216(2):281-6

Human laminin B1 chain. A multidomain protein with gene (LAMB1) locus in the q22 region of chromosome 7.
Pikkarainen T, Eddy R, Fukushima Y, Byers M, Shows T, Pihlajaniemi T, et al
J. Biol. Chem. 1987 Aug;262(22):10454-62

Human laminin B2 chain. Comparison of the complete amino acid sequence with the B1 chain reveals variability in sequence homology between different structural domains.
Pikkarainen T, Kallunki T, Tryggvason K
J. Biol. Chem. 1988 May;263(14):6751-8

The structural genes for alpha 1 and alpha 2 chains of human type IV collagen are divergently encoded on opposite DNA strands and have an overlapping promoter region.
Soininen R, Huotari M, Hostikka S, Prockop D, Tryggvason K
J. Biol. Chem. 1988 Nov;263(33):17217-20

The complete primary structure of the alpha 2 chain of human type IV collagen and comparison with the alpha 1(IV) chain.
Hostikka S, Tryggvason K
J. Biol. Chem. 1988 Dec;263(36):19488-93

Human basement membrane heparan sulfate proteoglycan core protein: a 467-kD protein containing multiple domains resembling elements of the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor.
Kallunki P, Tryggvason K
J. Cell Biol. 1992 Jan;116(2):559-71

Structure of the human laminin B1 chain gene.
Vuolteenaho R, Chow L, Tryggvason K
J. Biol. Chem. 1990 Sep;265(26):15611-6

A truncated laminin chain homologous to the B2 chain: structure, spatial expression, and chromosomal assignment.
Kallunki P, Sainio K, Eddy R, Byers M, Kallunki T, Sariola H, et al
J. Cell Biol. 1992 Nov;119(3):679-93

Complete primary structure of the human alpha 3(IV) collagen chain. Coexpression of the alpha 3(IV) and alpha 4(IV) collagen chains in human tissues.
Mariyama M, Leinonen A, Mochizuki T, Tryggvason K, Reeders S
J. Biol. Chem. 1994 Sep;269(37):23013-7

Structure of the human laminin alpha2-chain gene (LAMA2), which is affected in congenital muscular dystrophy.
Zhang X, Vuolteenaho R, Tryggvason K
J. Biol. Chem. 1996 Nov;271(44):27664-9

Primary structure, developmental expression, and immunolocalization of the murine laminin alpha4 chain.
Iivanainen A, Kortesmaa J, Sahlberg C, Morita T, Bergmann U, Thesleff I, et al
J. Biol. Chem. 1997 Oct;272(44):27862-8

Molecular cloning and tissue-specific expression of a novel murine laminin gamma3 chain.
Iivanainen A, Morita T, Tryggvason K
J. Biol. Chem. 1999 May;274(20):14107-11

Recombinant laminin-8 (alpha(4)beta(1)gamma(1)). Production, purification,and interactions with integrins.
Kortesmaa J, Yurchenco P, Tryggvason K
J. Biol. Chem. 2000 May;275(20):14853-9

Recombinant human laminin-10 (alpha5beta1gamma1). Production, purification, and migration-promoting activity on vascular endothelial cells.
Doi M, Thyboll J, Kortesmaa J, Jansson K, Iivanainen A, Parvardeh M, et al
J. Biol. Chem. 2002 Apr;277(15):12741-8

Contributions of the LG modules and furin processing to laminin-2 functions.
Smirnov S, McDearmon E, Li S, Ervasti J, Tryggvason K, Yurchenco P
J. Biol. Chem. 2002 May;277(21):18928-37

Laminin isoforms in tumor invasion, angiogenesis and metastasis.
Patarroyo M, Tryggvason K, Virtanen I
Semin. Cancer Biol. 2002 Jun;12(3):197-207

Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney.
Rossi M, Morita H, Sormunen R, Airenne S, Kreivi M, Wang L, et al
EMBO J. 2003 Jan;22(2):236-45

Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan.
Tran P, Tran-Lundmark K, Soininen R, Tryggvason K, Thyberg J, Hedin U
Circ. Res. 2004 Mar;94(4):550-8

Deletion of laminin-8 results in increased tumor neovascularization and metastasis in mice.
Zhou Z, Doi M, Wang J, Cao R, Liu B, Chan K, et al
Cancer Res. 2004 Jun;64(12):4059-63

Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice.
Zhou Z, Wang J, Cao R, Morita H, Soininen R, Chan K, et al
Cancer Res. 2004 Jul;64(14):4699-702

An endothelial laminin isoform, laminin 8 (alpha4beta1gamma1), is secreted by blood neutrophils, promotes neutrophil migration and extravasation, and protects neutrophils from apoptosis.
Wondimu Z, Geberhiwot T, Ingerpuu S, Juronen E, Xie X, Lindbom L, et al
Blood 2004 Sep;104(6):1859-66

Impeded interaction between Schwann cells and axons in the absence of laminin alpha4.
Wallquist W, Plantman S, Thams S, Thyboll J, Kortesmaa J, Lännergren J, et al
J. Neurosci. 2005 Apr;25(14):3692-700

A simplified laminin nomenclature.
Aumailley M, Bruckner-Tuderman L, Carter W, Deutzmann R, Edgar D, Ekblom P, et al
Matrix Biol. 2005 Aug;24(5):326-32

Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain-deficient mice.
Wang J, Hoshijima M, Lam J, Zhou Z, Jokiel A, Dalton N, et al
J. Biol. Chem. 2006 Jan;281(1):213-20

The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation.
Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, et al
Dev. Cell 2006 Mar;10(3):397-405

Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain-deficient mice.
Wang J, Hoshijima M, Lam J, Zhou Z, Jokiel A, Dalton N, et al
J. Biol. Chem. 2006 Jan;281(1):213-20

Basement Membrane Diseases

The group described the first human genetic BM diseases by showing mutations in type IV collagen in Alport syndrome (hereditary nephritis) and diffuse leiomyomatosis. Furthermore, the first laminin disease was demonstrated by finding mutations in the g2 chain of the laminin-5 isoform in junctional epidermolysis bullosa, and defects in the laminin a2 chain were shown to underlie congenital muscular dystrophy. The gene for congenital nephrotic syndrome was also found by positional cloning. The results of this work have enabled the development of DNA-based diagnostic methods for these diseases. At the present, members of the group are developing gene therapy for Alport syndrome in dogs, and they have been successful in obtaining efficient in vivo gene transfer into kidney glomeruli in experimental animals.

Some of the main complications of diabetes are microvascular changes (microangiopathy), which are thought to be the primary cause of severe diabetic kidney and eye complications. Microangiopathy may also contribute to skin ulcers and neuropathy that are frequent complications of diabetes as well. Nephropathy, that primarily affects the kidney glomeruli, has been shown to be genetically regulated. The research group carries out linkage analyses and association studies to find gene(s) that predispose to the dreadful diabetes complications. In collaboration with researchers in Finland, Iceland and Denmark, DNA samples from patients in these countries are analyzed to find loci harboring the gene(s). Identification of the diabetic nephropathy gene(s) would be of immense value for identifying patients with propensity of developing diabetes nephropathy and for improving treatment.

Selected publications

Identification of a distinct type IV collagen alpha chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome.
Hostikka S, Eddy R, Byers M, Höyhtyä M, Shows T, Tryggvason K
Proc. Natl. Acad. Sci. U.S.A. 1990 Feb;87(4):1606-10

Identification of mutations in the COL4A5 collagen gene in Alport syndrome.
Barker D, Hostikka S, Zhou J, Chow L, Oliphant A, Gerken S, et al
Science 1990 Jun;248(4960):1224-7

Complete amino acid sequence of the human alpha 5 (IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domain to cysteine in an Alport syndrome patient.
Zhou J, Hertz J, Leinonen A, Tryggvason K
J. Biol. Chem. 1992 Jun;267(18):12475-81

Alport syndrome and diffuse leiomyomatosis: deletions in the 5' end of the COL4A5 collagen gene.
Antignac C, Zhou J, Sanak M, Cochat P, Roussel B, Deschênes G, et al
Kidney Int. 1992 Nov;42(5):1178-83

Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors.
Zhou J, Mochizuki T, Smeets H, Antignac C, Laurila P, de Paepe A, et al
Science 1993 Aug;261(5125):1167-9

Mutations in the gamma 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa.
Pulkkinen L, Christiano A, Airenne T, Haakana H, Tryggvason K, Uitto J
Nat. Genet. 1994 Mar;6(3):293-7

Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5).
Aberdam D, Galliano M, Vailly J, Pulkkinen L, Bonifas J, Christiano A, et al
Nat. Genet. 1994 Mar;6(3):299-304

Structure of the human type IV collagen COL4A5 gene.
Zhou J, Leinonen A, Tryggvason K
J. Biol. Chem. 1994 Mar;269(9):6608-14

Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy.
Helbling-Leclerc A, Zhang X, Topaloglu H, Cruaud C, Tesson F, Weissenbach J, et al
Nat. Genet. 1995 Oct;11(2):216-8

Adenovirus-mediated gene transfer into kidney glomeruli using an ex vivo and in vivo kidney perfusion system - first steps towards gene therapy of Alport syndrome.
Heikkila P, Parpala T, Lukkarinen O, Weber M, Tryggvason K
Gene Ther. 1996 Jan;3(1):21-7

Mutations in type IV collagen genes and Alport phenotypes.
Tryggvason K
Contrib Nephrol 1996 ;117():154-71

Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain.
Allamand V, Sunada Y, Salih M, Straub V, Ozo C, Al-Turaiki M, et al
Hum. Mol. Genet. 1997 May;6(5):747-52

Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome.
Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, et al
Mol. Cell 1998 Mar;1(4):575-82

Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm.
Tryggvason K
J. Am. Soc. Nephrol. 1999 Nov;10(11):2440-5

Properly formed but improperly localized synaptic specializations in the absence of laminin alpha4.
Patton B, Cunningham J, Thyboll J, Kortesmaa J, Westerblad H, Edström L, et al
Nat. Neurosci. 2001 Jun;4(6):597-604

Adenovirus-mediated transfer of type IV collagen alpha5 chain cDNA into swine kidney in vivo: deposition of the protein into the glomerular basement membrane.
Heikkilä P, Tibell A, Morita T, Chen Y, Wu G, Sado Y, et al
Gene Ther. 2001 Jun;8(11):882-90

Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome.
Liu L, Doné S, Khoshnoodi J, Bertorello A, Wartiovaara J, Berggren P, et al
Hum. Mol. Genet. 2001 Nov;10(23):2637-44

Congenital nephrotic syndromes.
Khoshnoodi J, Tryggvason K
Curr. Opin. Genet. Dev. 2001 Jun;11(3):322-7

Molecular basis of glomerular permselectivity.
Tryggvason K, Wartiovaara J
Curr. Opin. Nephrol. Hypertens. 2001 Jul;10(4):543-9

Alport's syndrome, Goodpasture's syndrome, and type IV collagen.
Hudson B, Tryggvason K, Sundaramoorthy M, Neilson E
N. Engl. J. Med. 2003 Jun;348(25):2543-56

Causes and consequences of proteinuria: the kidney filtration barrier and progressive renal failure.
Tryggvason K, Pettersson E
J. Intern. Med. 2003 Sep;254(3):216-24

Altered ultrastructural distribution of nephrin in minimal change nephrotic syndrome.
Wernerson A, Dunér F, Pettersson E, Widholm S, Berg U, Ruotsalainen V, et al
Nephrol. Dial. Transplant. 2003 Jan;18(1):70-6

Nephrin promotes cell-cell adhesion through homophilic interactions.
Khoshnoodi J, Sigmundsson K, Ofverstedt L, Skoglund U, Obrink B, Wartiovaara J, et al
Am. J. Pathol. 2003 Dec;163(6):2337-46

Defective trafficking of nephrin missense mutants rescued by a chemical chaperone.
Liu X, Doné S, Yan K, Kilpeläinen P, Pikkarainen T, Tryggvason K
J. Am. Soc. Nephrol. 2004 Jul;15(7):1731-8

Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography.
Wartiovaara J, Ofverstedt L, Khoshnoodi J, Zhang J, Mäkelä E, Sandin S, et al
J. Clin. Invest. 2004 Nov;114(10):1475-83

Characterization of the interactions of the nephrin intracellular domain.
Liu X, Kilpeläinen P, Hellman U, Sun Y, Wartiovaara J, Morgunova E, et al
FEBS J. 2005 Jan;272(1):228-43

Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q.
Osterholm A, He B, Pitkaniemi J, Albinsson L, Berg T, Sarti C, et al
Kidney Int. 2007 Jan;71(2):140-5

Functional genomics of the kidney glomerulus

The human kidney contains about one million filtration units called glomeruli. A glomerulus consists of a bag-like Bowmans capsule containing several capillaries (glomerular tuft), the walls of which constitute the filter system. The plasma filtrate is led to the proximal tubule, while the unfiltered blood returns to the blood circulation. The filtration barrier of the capillary wall contains a fenestrated endothelium, the glomerular basement membrane (GBM), and the podocytes with their interdigitating foot processes. The slit diaphragm is the renal ultraThe human kidneyfilter that is located between the foot processes. Until only recently, the molecular nature of this filter was unknown, but now nephrin, Neph-1 and FAT have been identified as its crucial components. Abnormalities in the glomerulus often lead to progressive proteinuria and renal failure that needs to be treated by hemodialysis and kidney transplantation. Our identification of the nephrin gene, that is mutated in congenital nephrotic syndrome, was a groundbraking result, as it provided new insight into the molecular nature of the renal ultrafilter, the structure of which had been a mystery for decades. Although a few slit membrane components have now been identified, many aspects of the glomerulus and particularly the pathogenesis of different types of glomerulopathies are still poorly understood. Our glomerulus functional genomics project aims at providing new information into the biology and pathology of the renal glomerulus.

Together with Christer Betsholtz, the group carries out an extensive project on the functional genomics of the renal glomerulus and its diseases. The entire mouse glomerulus transcriptome has been characterized, and over 300 novel transcripts and proteins highly specific for the glomerulus have been identified. To study the functions of these proteins, gene knockouts are being made in mice and knockdowns are being done on a large scale in collaboration with Majumdars group. Antibodies have been made against the proteins in collaboration with Mathias Uhléns group at the Royal Institute of Technology in Stockholm. In parallel, the proteome and its changes are studied in renal disease processes in mice. These studies are likely to lead to extensive new knowledge on the kidney filter system and its diseases, and they can form a firm basis for the development on diagnostics and drug development.

Selected publications

Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome.
Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, et al
Mol. Cell 1998 Mar;1(4):575-82

Nephrin is specifically located at the slit diaphragm of glomerular podocytes.
Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestilä M, Jalanko H, et al
Proc. Natl. Acad. Sci. U.S.A. 1999 Jul;96(14):7962-7

Primary structure of mouse and rat nephrin cDNA and structure and expression of the mouse gene.
Putaala H, Sainio K, Sariola H, Tryggvason K
J. Am. Soc. Nephrol. 2000 Jun;11(6):991-1001

Role of nephrin in cell junction formation in human nephrogenesis.
Ruotsalainen V, Patrakka J, Tissari P, Reponen P, Hess M, Kestilä M, et al
Am. J. Pathol. 2000 Dec;157(6):1905-16

The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death.
Putaala H, Soininen R, Kilpeläinen P, Wartiovaara J, Tryggvason K
Hum. Mol. Genet. 2001 Jan;10(1):1-8

Alport's syndrome, Goodpasture's syndrome, and type IV collagen.
Hudson B, Tryggvason K, Sundaramoorthy M, Neilson E
N. Engl. J. Med. 2003 Jun;348(25):2543-56

Causes and consequences of proteinuria: the kidney filtration barrier and progressive renal failure.
Tryggvason K, Pettersson E
J. Intern. Med. 2003 Sep;254(3):216-24

Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography.
Wartiovaara J, Ofverstedt L, Khoshnoodi J, Zhang J, Mäkelä E, Sandin S, et al
J. Clin. Invest. 2004 Nov;114(10):1475-83

How does the kidney filter plasma?
Tryggvason K, Wartiovaara J
Physiology (Bethesda) 2005 Apr;20():96-101

Large-scale identification of genes implicated in kidney glomerulus development and function.
Takemoto M, He L, Norlin J, Patrakka J, Xiao Z, Petrova T, et al
EMBO J. 2006 Mar;25(5):1160-74

Thin basement membrane nephropathy.
Tryggvason K, Patrakka J
J. Am. Soc. Nephrol. 2006 Mar;17(3):813-22

Hereditary proteinuria syndromes and mechanisms of proteinuria.
Tryggvason K, Patrakka J, Wartiovaara J
N. Engl. J. Med. 2006 Mar;354(13):1387-401

Nck links nephrin to actin in kidney podocytes.
Tryggvason K, Pikkarainen T, Patrakka J
Cell 2006 Apr;125(2):221-4

Expression and subcellular distribution of novel glomerulus-associated proteins dendrin, ehd3, sh2d4a, plekhh2, and 2310066E14Rik.
Patrakka J, Xiao Z, Nukui M, Takemoto M, He L, Oddsson A, et al
J. Am. Soc. Nephrol. 2007 Mar;18(3):689-97

Nephrin--a unique structural and signaling protein of the kidney filter.
Patrakka J, Tryggvason K
Trends Mol Med 2007 Sep;13(9):396-403

Matrix metalloproteinases and Cancer

Matrix metalloproteinases (MMPs) are a large family of enzymes that degrade the extracellular matrix. Of those enzymes, MMP-2 and MMP-9, also called type IV collagenases or gelatinases, are related enzymes that break down type IV collagen. Our group first identified and purified MMP-2 and has for long studied different aspects of both MMP-2 and MMP-9. We recently succeeded in determining the first full structure of a pro-MMP (pro-MMP-2) and its free inhibitor TIMP-2, and have also determined the structure of a pro-MMP-2/TIMP-2 complex. The crystal structures can be used for development of novel specific enzyme inhibitors. The group also carries out studies on the regulation of MMP genes, and has inactivated the gene for the membrane bound MT1-MMP to study its normal role and involvement in diseases. Functions of some MMPs are studied in zebrafish.

Selected publications

Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1 A resolution.
Tuuttila A, Morgunova E, Bergmann U, Lindqvist Y, Maskos K, Fernandez-Catalan C, et al
J. Mol. Biol. 1998 Dec;284(4):1133-40

Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed.
Morgunova E, Tuuttila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G, et al
Science 1999 Jun;284(5420):1667-70

Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.
Zhou Z, Apte S, Soininen R, Cao R, Baaklini G, Rauser R, et al
Proc. Natl. Acad. Sci. U.S.A. 2000 Apr;97(8):4052-7

Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.
Morgunova E, Tuuttila A, Bergmann U, Tryggvason K
Proc. Natl. Acad. Sci. U.S.A. 2002 May;99(11):7414-9

Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice.
Pendás A, Zhou Z, Cadiñanos J, Freije J, Wang J, Hultenby K, et al
Nat. Genet. 2002 May;31(1):94-9

Deletion of laminin-8 results in increased tumor neovascularization and metastasis in mice.
Zhou Z, Doi M, Wang J, Cao R, Liu B, Chan K, et al
Cancer Res. 2004 Jun;64(12):4059-63

Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice.
Zhou Z, Wang J, Cao R, Morita H, Soininen R, Chan K, et al
Cancer Res. 2004 Jul;64(14):4699-702

Genomic instability in laminopathy-based premature aging.
Liu B, Wang J, Chan K, Tjia W, Deng W, Guan X, et al
Nat. Med. 2005 Jul;11(7):780-5

Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation.
Varela I, Cadiñanos J, Pendás A, Gutiérrez-Fernández A, Folgueras A, Sánchez L, et al
Nature 2005 Sep;437(7058):564-8

Membrane type 1-matrix metalloproteinase is regulated by chemokines monocyte-chemoattractant protein-1/ccl2 and interleukin-8/CXCL8 in endothelial cells during angiogenesis.
Gálvez B, Genís L, Matías-Román S, Oblander S, Tryggvason K, Apte S, et al
J. Biol. Chem. 2005 Jan;280(2):1292-8

Macrophage MARCO receptor

A novel MAcrophage Receptor with COllagenous structure (MARCO) was identified by the group using molecular cloning. This receptor was shown to bind bacteria and LPS, but not yeast. MARCO is normally expressed in certain macrophages of the spleen and lymph nodes, but is strongly upregulated upon systemic bacterial infections. MARCO and its involvement in host defense is extensively being studied from a number of angles, including cellular biology, knockout mice and gene regulation. We have also cloned and are functionally characterizing a novel scavenger receptor (SCARA5).

Selected publications

Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages.
Elomaa O, Kangas M, Sahlberg C, Tuukkanen J, Sormunen R, Liakka A, et al
Cell 1995 Feb;80(4):603-9

Structure of the human macrophage MARCO receptor and characterization of its bacteria-binding region.
Elomaa O, Sankala M, Pikkarainen T, Bergmann U, Tuuttila A, Raatikainen-Ahokas A, et al
J. Biol. Chem. 1998 Feb;273(8):4530-8

Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo.
van der Laan L, Döpp E, Haworth R, Pikkarainen T, Kangas M, Elomaa O, et al
J. Immunol. 1999 Jan;162(2):939-47

Structure and chromosomal localization of the human and murine genes for the macrophage MARCO receptor.
Kangas M, Brännström A, Elomaa O, Matsuda Y, Eddy R, Shows T, et al
Genomics 1999 May;58(1):82-9

Expression of macrophage MARCO receptor induces formation of dendritic plasma membrane processes.
Pikkarainen T, Brännström A, Tryggvason K
J. Biol. Chem. 1999 Apr;274(16):10975-82

Role of the scavenger receptor MARCO in alveolar macrophage binding of unopsonized environmental particles.
Palecanda A, Paulauskis J, Al-Mutairi E, Imrich A, Qin G, Suzuki H, et al
J. Exp. Med. 1999 May;189(9):1497-506

Arginine residues in domain V have a central role for bacteria-binding activity of macrophage scavenger receptor MARCO.
Brännström A, Sankala M, Tryggvason K, Pikkarainen T
Biochem. Biophys. Res. Commun. 2002 Feb;290(5):1462-9

The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles.
Arredouani M, Yang Z, Ning Y, Qin G, Soininen R, Tryggvason K, et al
J. Exp. Med. 2004 Jul;200(2):267-72

Characterization of recombinant soluble macrophage scavenger receptor MARCO.
Sankala M, Brännström A, Schulthess T, Bergmann U, Morgunova E, Engel J, et al
J. Biol. Chem. 2002 Sep;277(36):33378-85

Defective microarchitecture of the spleen marginal zone and impaired response to a thymus-independent type 2 antigen in mice lacking scavenger receptors MARCO and SR-A.
Chen Y, Pikkarainen T, Elomaa O, Soininen R, Kodama T, Kraal G, et al
J. Immunol. 2005 Dec;175(12):8173-80

Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis.
Martens J, Kzhyshkowska J, Falkowski-Hansen M, Schledzewski K, Gratchev A, Mansmann U, et al
J. Pathol. 2006 Mar;208(4):574-89

A phage display screen and binding studies with acetylated low density lipoprotein provide evidence for the importance of the scavenger receptor cysteine-rich (SRCR) domain in the ligand-binding function of MARCO.
Chen Y, Sankala M, Ojala J, Sun Y, Tuuttila A, Isenman D, et al
J. Biol. Chem. 2006 May;281(18):12767-75

Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II.
Dahl M, Bauer A, Arredouani M, Soininen R, Tryggvason K, Kleeberger S, et al
J. Clin. Invest. 2007 Mar;117(3):757-64

Research group

Anna DomogatskayaSenior researcher
Jing GuoResearch assistant on study grant
Bing HeSenior researcher
Yugo ItoAssociated
Kan KatayamaSenior lab manager
Ann Sofie NilssonBiomedical scientist
Juha OjalaPostdoc
Olle RengbyPostdoc
Sergey RodinAssistant professor
Karl TryggvasonProfessor
Susanne VirdingBiomedical scientist
Lijun YangAssociated
Anne-May ÖsterholmSenior researcher