DESCRIPTION OF CURRENT RESEARCH

We study the ways in which intracellular signal transduction and membrane trafficking in endocytosis are integrated at the molecular level. We focus on proteins that play well-known roles in endocytosis to investigate their involvement in various signaling pathways and their impact on patterns of gene expression. Our efforts initially focused on studying the endosomal and nuclear roles of APPL proteins. In recent years, we broadened our interests to other multifunctional proteins that act in endocytosis and signaling. The specific projects that are developed by our group seek to answer the following questions:

  • What is the role of endosomal compartments in the trafficking and signaling of receptors for growth factors and cytokines?

  • How does the endocytic trafficking of receptors impinge on the patterns of gene expression in different signaling pathways?

  • What are the consequences of endosomal dysfunction in the cell and in the context of oncogenesis?

Endocytosis was first viewed simply as a mechanism of signal termination through the downregulation and degradation of surface receptors. However, more recent data indicate that endosomal compartments and their resident proteins play an important role in transmitting intracellular signals by transporting ligand-receptor complexes and affecting their activity inside the cell (Sadowski et al., Exp Cell Res, 2009; Miaczynska and Bar-Sagi, Curr Opin Cell Biol, 2010; Hupalowska and Miaczynska, Traffic, 2012; Miaczynska, Cold Spring Harb Perspect Biol, 2013; Cendrowski et al., Cytokine Growth Factor Rev, 2016; Szymanska et al., Semin Cell Dev Biol, 2018). Moreover, several endocytic proteins can undergo nucleocytoplasmic shuttling and interact with nuclear molecules that are involved in transcription or chromatin remodeling, changing their localization or activity, and thus may directly modulate the levels or specificity of gene transcription (Pilecka et al., Eur J Cell Biol, 2007). Importantly, some such dualfunction endocytic and nuclear proteins affect cell proliferation or act as tumor suppressors, or their expression changes in human cancers (Pyrzyńska et al., Mol Oncol, 2009).

In one of our previous projects, we identified four components of endosomal sorting complexes required for transport (ESCRTs) as novel inhibitors of nuclear factor-κB (NF-κB) signaling (Mamińska et al., Sci Signal, 2016). We found that the depletion of several ESCRT subunits in the absence of cytokine stimulation potently activated NF-κB signaling in cultured human cells, zebrafish embryos, and fat bodies in flies. These effects depended on cytokine receptors, such as lymphotoxin β receptor (LTβR) and tumor necrosis factor receptor 1 (TNFR1). We demonstrated that upon the depletion of ESCRT subunits, both receptors became concentrated on and signaled from endosomes. The endosomal accumulation of LTβR induced its ligandindependent oligomerization and inflammatory NF-κB signaling. We proposed that ESCRTs constitutively control the distribution of cytokine receptors in their ligand-free state to restrict their signaling.

As a follow-up of this work, we further investigated the mechanisms of intracellular trafficking and inflammatory signaling by LTβR (Banach-Orłowska et al., J Cell Sci, 2018). We showed that various types of endolysosomal dysfunction lead to the accumulation of ligand-free LTβR on endosomes, but the exact topology of the receptor within these compartments determines whether NF-κB signaling is induced or prevented. Most recently, we focused on the ligand-induced trafficking and signaling of LTβR (Banach-Orłowska et al., Cell Commun Signal, 2019). We found that plasma membrane cholesterol content is important for proper LTβR internalization to prevent overstimulation of the NF-κB pathway and the overproduction of cytokines. We proposed that drugs that modulate cholesterol levels could potentially improve the efficacy of LTβR-based therapies for autoimmune diseases and cancer.

In another recently published study, we uncovered an exciting connection between two ESCRT accessory proteins (VPS4A and VPS4B) and cancer (Szymańska et al., EMBO Mol Med, 2020). In humans, these ubiquitous ATPases are encoded by VPS4A and VPS4B paralogous genes. Together with other ESCRT subunits, VPS4 proteins participate in the remodeling of biological membranes that occurs during endocytosis and other intracellular processes, such as cytokinesis and exosome release. Thus, VPS4A and VPS4B are of importance for cellular homeostasis, and as enzymes they may represent convenient drug targets. By first exploring the publicly available Cancer Genome Atlas, we found that the VPS4B gene is frequently lost in many cancer types, notably colorectal cancer, along with a larger part of chromosome 18. Our clinical collaborators at the Maria Skłodowska-Curie Institute-Oncology Centre in Warsaw confirmed lower levels of VPS4B protein in tumor samples from colorectal cancer patients compared with healthy colon tissue. Using cancer cell lines that were grown in vitro and in vivo, we found that VPS4A and VPS4B paralogs were synthetically lethal, in which their simultaneous depletion (VPS4A+VPS4B) caused cell death, whereas the loss of any single paralog (VPS4A or VPS4B) was well tolerated. Our study demonstrated that VPS4B-deficient cancer cells are selectively vulnerable to perturbations of VPS4A activity. Importantly, we also discovered that dying cells that lacked both VPS4A and VPS4B proteins induced a strong inflammatory response that could evoke an anti-tumor reaction in the organism, thus supporting a positive therapeutic outcome (Fig. 1). In summary, we provided a rationale for future work to develop a VPS4 inhibitor as a putative precision therapy for patients with VPS4B-deficient cancers, such as colorectal cancer.

fig.1

fig.1. Model of synthetic lethal interaction between VPS4A and VPS4B. (Left) In normal cells, both VPS4A and VPS4B act redundantly in several essential intracellular processes. The single depletion of either paralog (e.g., VPS4A) is well tolerated because the unperturbed expression of the other paralog alone (e.g., VPS4B) can compensate for its downregulated counterpart. (Right) Cells that have lost VPS4B expression (e.g., because of oncogenic genome rearrangements) rely exclusively on VPS4A activity. The inactivation of VPS4A in these cells leads to synthetic lethality, accompanied by the strong induction of an inflammatory response and the release of immunogenic DAMPs. Immunomodulatory molecules that are released by dying VPS4A+VPS4B-deficient cancer cells can elicit paracrine effects on primary immune cells, such as reprogramming of macrophages toward the M1 anti-tumor phenotype. Author: Ewelina Szymańska (after Szymańska et al., EMBO Mol Med, 2020)

 

mmiaczynska

Marta Miączyńska,  PhD, Professor 

Correspondence address:
Laboratory of Cell Biology
International Institute of Molecular and Cell Biology
4 Ks. Trojdena Street, 02-109 Warsaw, Poland
Email: This email address is being protected from spambots. You need JavaScript enabled to view it. 
tel: +48 (22) 597 0725; fax: +48 (22) 597 0715

DEGREES

2013 - Professor of Biological Sciences, nomination by the President of the Republic of Poland
2008 - DSc Habil in Cell Biology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
1997 - PhD in Genetics, University of Vienna, Austria
1993 - MSc in Molecular Biology, Jagiellonian University, Cracow, Poland
1991 - BSc in Biological Sciences, University of Wolverhampton, UK

 

PROFESSIONAL EMPLOYMENT

2018-present - Director, International Institute of Molecular and Cell Biology in Warsaw, Poland
2014-2015 - Deputy Director for Science, International Institute of Molecular and Cell Biology in Warsaw, Poland
2013-2014 - Deputy Director, International Institute of Molecular and Cell Biology in Warsaw, Poland
2005-present - Professor, Head of Laboratory of Cell Biology, International Institute of Molecular and Cell Biology in Warsaw, Poland

RESEARCH TRAINING

2001-2005 - Senior Postdoctoral Fellow, Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG), Dresden, Germany
1997-2000 - Postdoctoral training, European Molecular Biology Laboratory, Heidelberg, Germany
1993-1996 - PhD studies, Institute of Microbiology and Genetics, University of Vienna, Austria
1990-1991 - Exchange Student, University of Wolverhampton, UK

HONORS, PRIZES AND AWARDS

2020 - Corresponding Member, Polish Academy of Sciences
2019 - Member, Academia Europaea
2017 - Member, European Molecular Biology Organization
2016-2018 - Member, Council of the National Science Centre
2016 - TEAM, Foundation for Polish Science
2012 - MAESTRO, National Science Centre
2011 - Polish-Swiss Research Programme grant
2007 - Habilitation Fellowship of L’Oréal Poland for Women in Science
2006-2012 - International Senior Research Fellowship, Wellcome Trust
2006-2010 - International Research Scholar, Howard Hughes Medical Institute, USA
2006-2010 - Partner Group grant, Max Planck Society, Germany
2001-2004 - Postdoctoral Fellowship, Max Planck Society, Germany
1999-2000 - Long-Term Postdoctoral Fellowship, Human Frontier Science Program Organization
1998-1999 - Erwin Schrödinger Postdoctoral Fellowship, Austrian Science Fund
1993-1996 - Bertha von Suttner PhD Scholarship, Austrian Ministry of Science
1990-1991 - Studentship, European Community Tempus Scheme

DOCTORATES DEFENDED UNDER LAB LEADER’S SUPERVISION

M. Olchowik, A. Urbańska, A. Hupałowska, Ł. Sadowski, A. Mamińska, A. Toruń, K. Jastrzębski.

team2019

Lab Leader:

  • Marta Miączyńska, PhD, Professor

Senior Researchers:

  • Ewelina Szymańska, PhD

  • Daria Zdżalik-Bielecka, PhD

  • Jarosław Cendrowski, PhD

Postdoctoral Researchers:

  • Ranjana Maurya, PhD

Research Assistant:

  • Patrycja Daszczuk, MSc

PhD Students:

  • Marta Wróbel, MSc

  • Malwina Grębowicz, MSc

  • Marta Jakubik, MSc

Undergraduate Students:

  • Bartosz Jary

Lab Technician:

  • Monika Matuszczyk (part-time)

Laboratory Support Specialist:

  • Alicja Machaj, MSc

  • Renata Wyszyńska, MSc (leave of absence)

2022

Endocytic trafficking of GAS6-AXL complexes is associated with sustained AKT activation.

Poświata A, Kozik K, Miączyńska M, Zdżalik-Bielecka D.

Cell Mol Life Sci.. 2022

Tollip-deficient zebrafish display no abnormalities in development, organ morphology or gene expression in response to lipopolysaccharide.

Wolińska-Nizioł L, Romaniuk K, Wojciechowska K, Surga K, Kamaszewski M, Szudrowicz H, Miączyńska M.

FEBS Open Bio.. 2022

The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells.

Oroń M, Grochowski M, Jaiswar A, Legierska J, Jastrzębski K, Nowak-Niezgoda M, Kołos M, Kaźmierczak W, Olesiński T, Lenarcik M, Cybulska M, Mikula M, Żylicz A, Miączyńska M, Zettl K, Wiśniewski JR, Walerych D.

Cell Rep.. 2022

Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes.

Sekar R, Motzler K, Kwon Y, Novikoff A, Jülg J, Najafi B, Wang S, Warnke AL, Seitz S, Hass D, Gancheva S, Kahl S, Yang B, Finan B, Schwarz K, Okun JG, Roden M, Blüher M, Müller TD, Krahmer N, Behrends C, Plettenburg O, Miaczynska M, Herzig S, Zeigerer A.

Cell Metab.. 2022

Bemcentinib and gilteritinib inhibit cell growth and impair the endo-lysosomal and autophagy systems in an AXL-independent manner.

Zdzalik-Bielecka D, Kozik K, Poswiata A, Jastrzebski K, Jakubik M, Miaczynska M.

Mol Cancer Res. . 2022

ESCRT-I fuels lysosomal degradation to restrict TFEB/TFE3 signaling via the Rag-mTORC1 pathway.

Wróbel M, Cendrowski J, Szymańska E, Grębowicz-Maciukiewicz M, Budick-Harmelin N, Macias M, Szybińska A, Mazur M, Kolmus K, Goryca K, Dąbrowska M, Paziewska A, Mikula M, Miączyńska M.

Life Sci Alliance. 2022

2021

Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses.

Kolmus K, Erdenebat P, Szymańska E, Stewig B, Goryca K, Derezinska-Wolek E, Szumera-Cieckiewicz A, Brewinska-Olchowik M, Piwocka K, Prochorec-Sobieszek M, Mikula M, Miaczynska M.

J Cell Sci.. 2021

Dissecting biological activities of fibroblast growth factor receptors by the coiled-coil-mediated oligomerization of FGF1.

Porebska N, Pozniaka M, Krzyscik MA, Knapika A, Czyrek A, Kucinska M, Jastrzebski K, Zakrzewska M, Otlewski J, Opalinski L.

Int J Biol Macromol.. 2021

The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling, macropinocytosis, and cancer-cell invasion.

Zdżalik-Bielecka D, Poświata A, Kozik K, Jastrzębski K, Schink KO, Brewińska-Olchowik M, Piwocka K, Stenmark H, Miączyńska M.

Proc Natl Acad Sci USA. 2021

Modular self-assembly system for development of oligomeric, highly internalizing and potent cytotoxic conjugates targeting fibroblast growth factor receptors.

Poźniak M, Porębska N, Jastrzębski K, Krzyścik MA, Kucińska M, Zarzycka W, Barbach A, Zakrzewska M, Otlewski J, Miączyńska M, Opaliński Ł.

J Biomed Sci.. 2021

2020

Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer.

Szymańska E, Nowak P, Kolmus K, Cybulska M, Goryca K, Derezińska-Wołek E, Szumera-Ciećkiewicz A, Brewińska-Olchowik M, Grochowska A, Piwocka K, Prochorec-Sobieszek M, Mikula M, Miączyńska M.

EMBO Mol Med.. 2020

Membrane Trafficking: Vesicle Formation, Cargo Sorting and Fusion.

 Miaczynska M, Munson M.

Mol Biol Cell. . 2020

FGFR1 Clustering With Engineered Tetravalent Antibody Improves the Efficiency and Modifies the Mechanism of Receptor Internalization.

Pozniak M, Sokolowska-Wedzina A, Jastrzebski K, Szymczyk J, Porebska N, Krzyscik MA, Zakrzewska M, Miaczynska M, Otlewski J, Opalinski L.

Mol Oncol. . 2020

Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells.

Cendrowski J, Kaczmarek M, Mazur M, Kuzmicz-Kowalska K, Jastrzebski K, Brewinska-Olchowik M, Kominek A, Piwocka K, Miaczynska M.

eLife . 2020

Splicing variants of an endocytic regulator, BMP2K, differentially control autophagic degradation in erythroid cells.

Cendrowski J, Miaczynska M.

Autophagy. 2020

Clathrin- and dynamin-dependent endocytosis limits canonical NF-κB signaling triggered by lymphotoxin β receptor.

Maksymowicz M, Miączyńska M, Banach-Orłowska M.

Cell Commun Signal.. 2020

2019

Cholesterol restricts lymphotoxin β receptor-triggered NF-κB signaling.

Banach-Orłowska M, Wyszyńska R, Pyrzyńska B, Maksymowicz M, Gołąb J, Miączyńska M.

Cell Commun Signal.. 2019

2018

The topology of lymphotoxin β receptor accumulated upon endolysosomal dysfunction dictates the NF-κB signaling outcome.

Banach-Orłowska M, Jastrzębski K, Cendrowski JMaksymowicz M, Wojciechowska K, Korostyński M, Moreau D, Gruenberg J, Miaczynska M.

J Cell Sci.. 2018

Integration of the Endocytic System into the Network of Cellular Functions.

Budick-Harmelin N, Miaczynska M.

Prog Mol Subcell Biol.. 2018

2017

Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling

Jastrzębski K, Zdżalik-Bielecka D, Mamińska A, Kalaidzidis Y, Hellberg C, Miaczynska M

J Cell Sci.. 2017

Endosomal "sort" of signaling control: The role of ESCRT machinery in regulation of receptor-mediated signaling pathways.

Szymanska E, Budick-Harmelin N, Miaczynska M.

Semin Cell Dev Biol.. 2017

2016

Impaired dynamin 2 function leads to increased AP-1 transcriptional activity through the JNK/c-Jun pathway

Szymanska E, Skowronek A, Miaczynska M

Cell Signal. 2016

ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors

Mamińska A, Bartosik A, Banach-Orłowska M, Pilecka I, Jastrzębski K, Zdżalik-Bielecka D, Castanon I, Poulain M, Neyen C, Wolińska-Nizioł L, Toruń A, Szymańska E, Kowalczyk A, Piwocka K, Simonsen A, Stenmark H, Fürthauer M, González-Gaitán M, Miaczynska M

Sci Signal. 2016

APPL proteins promote TGFβ-induced nuclear transport of the TGFβ type I receptor intracellular domain

Song J, Mu Y, Li C, Bergh A, Miaczynska M, Heldin CH, Landström M

Oncotarget. 2016

Endocytic regulation of cytokine receptor signaling

Cendrowski J, Mamińska A, Miaczynska M

Cytokine Growth Factor Rev. 2016

Genome-wide co-localization of active EGFR and downstream ERK pathway kinases mirrors mitogen-inducible RNA polymerase 2 genomic occupancy.

Mikula M, Skrzypczak M, Goryca K, Paczkowska K, Ledwon JK, Statkiewicz M, Kulecka M, Grzelak M, Dabrowska M, Kuklinska U, Karczmarski J, Rumienczyk I, Jastrzebski K, Miaczynska M, Ginalski K, Bomsztyk K, Ostrowski J.

Nucleic Acids Res. 2016

Lipid peroxidation in face of DNA damage, DNA repair and other cellular processes

Tudek B, Zdżalik-Bielecka D, Tudek A, Kosicki K, Fabisiewicz A, Speina E

Free Radic Biol Med. 2016

2015

Endocytic adaptor protein Tollip inhibits canonical Wnt signaling

Torun A, Szymańska E, Castanon I, Wolińska-Nizioł L, Bartosik A, Jastrzębski K, Miętkowska M, González-Gaitán M, Miaczynska M

PLoS One. 2015

APPL1 endocytic adaptor as a fine tuner of Dvl2-induced transcription

Banach-Orlowska M, Szymanska E, Miaczynska M

FEBS Lett. 2015

APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments

Kalaidzidis I, Miaczynska M, Brewińska-Olchowik M, Hupalowska A, Ferguson C, Parton RG, Kalaidzidis Y, Zerial M

J Cell Biol. 2015

Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome

Kolanczyk M, Krawitz P, Hecht J, Hupalowska A, Miaczynska M, Marschner K, Schlack C, Emerich D, Kobus K, Kornak U, Robinson PN, Plecko B, Grangl G, Uhrig S, Mundlos S, Horn D

Eur J Hum Genet. 2015

2014

Labeling of platelet-derived growth factor by reversible biotinylation to visualize its endocytosis by microscopy

Sadowski Ł, Jastrzębski K, Purta E, Hellberg C, Miaczynska M

Methods Enzymol.. 2014

2013

Multifunctional protein APPL2 contributes to survival of human glioma cells

Pyrzynska B, Banach-Orlowska M, Teperek-Tkacz M, Miekus K, Drabik G, Majka M, Miaczynska M

Mol Oncol.. 2013

Dynamin Inhibitors Impair Endocytosis and Mitogenic Signaling of PDGF

Sadowski L, Jastrzębski K, Kalaidzidis Y, Heldin CH, Hellberg C, Miaczynska M

Traffic. 2013

Effects of membrane trafficking on signaling by receptor tyrosine kinases

Miaczynska M

Cold Spring Harb Perspect Biol.. 2013

2012

The new faces of endocytosis in signaling

Hupalowska A, Miaczynska M

Traffic. 2012

APPL1 regulates basal NF-κB activity by stabilizing NIK

Hupalowska A, Pyrzynska B, Miaczynska M

J Cell Sci. 2012

P14ARF inhibits human glioblastoma-induced angiogenesis by upregulating the expression of TIMP3

Zerrouqi A, Pyrzynska B, Febbraio M, Brat DJ, Van Meir EG

J Clin Invest.. 2012

Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

Winiarska M, Nowis D, Bil J, Glodkowska-Mrowka E, Muchowicz A, Wanczyk M, Bojarczuk K, Dwojak M, Firczuk M, Wilczek E, Wachowska M, Roszczenko K, Miaczynska M, Chlebowska J, Basak GW, Golab J

J Biol Chem. 2012

2011

Biochemical characterization of APPL endosomes: the role of annexin A2 in APPL membrane recruitment

Urbanska A, Sadowski L, Kalaidzidis Y, Miaczynska M

Traffic. 2011

Recruitment of APPL1 to ubiquitin-rich aggresomes in response to proteasomal impairment

Pilecka I, Sadowski L, Kalaidzidis Y, Miaczynska M

Exp Cell Res. 2011

2010

Signaling endosomes: seeing is believing

Miaczynska M, Bar-Sagi D

Curr Opin Cell Biol. 2010

2009

Endocytic proteins in the regulation of nuclear signaling, transcription and tumorigenesis

Pyrzynska B, Pilecka I, Miaczynska M

Mol Oncol. 2009

Endosomal adaptor proteins APPL1 and APPL2 are novel activators of beta-catenin/TCF-mediated transcription.

Rashid S, Pilecka I, Torun A, Olchowik M, Bielinska B, Miaczynska M

J Biol Chem. 2009

Signaling from endosomes: location makes a difference.

Sadowski L, Pilecka I, Miaczynska M

Exp Cell Res. 2009

Functional characterization of the interactions between endosomal adaptor protein APPL1 and the NuRD co-repressor complex

Banach-Orlowska M, Pilecka I, Torun A, Pyrzynska B, Miaczynska M

Biochem J. 2009

[Effectors of GTPase Rab5 in endocytosis and signal transduction]

Olchowik M, Miaczyńska M

Postepy Biochem. 2009

Reconstitution of Rab- and SNARE-dependent membrane fusion by synthetic endosomes.

Ohya T, Miaczynska M, Coskun U, Lommer B, Runge A, Drechsel D, Kalaidzidis Y, Zerial M

Nature. 2009

2008

Mechanisms and functions of endocytosis.

Miaczynska M, Stenmark H

J Cell Biol. 2008

On the transition from the meiotic to mitotic cell cycle during early mouse development.

Kubiak JZ, Ciemerych MA, Hupalowska A, Sikora-Polaczek M, Polanski Z

Int J Dev Biol. 2008

2007

Nuclear functions of endocytic proteins

Pilecka I, Banach-Orlowska M, Miaczynska M

Eur J Cell Biol. 2007