Project acronym CANCER SIGNALOSOMES
Project Spatially and temporally regulated membrane complexes in cancer cell invasion and cytokinesis
Researcher (PI) Johanna Ivaska
Host Institution (HI) TEKNOLOGIAN TUTKIMUSKESKUS VTT
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.
Summary
Cancer progression, characterized by uncontrolled proliferation and motility of cells, is a complex and deadly process. Integrins, a major cell surface adhesion receptor family, are transmembrane proteins known to regulate cell behaviour by transducing extracellular signals to cytoplasmic protein complexes. We and others have shown that recruitment of specific protein complexes by the cytoplasmic domains of integrins is important in tumorigenesis. Here our aim is to study three interrelated processes in cancer progression which involve integrin signalling, but which have not been elucidated earlier at all. 1) Integrins in cell division (cytokinesis). Since coordinated action of the cytoskeleton and membranes is needed both for cell division and motility, shared integrin functions can regulate both events. 2) Dynamic integrin signalosomes at the leading edge of invading cells. Spatially and temporally regulated, integrin-protein complexes at the front of infiltrating cells are likely to dictate the movement of cancer cells in tissues. 3) Transmembrane segments of integrins as scaffolds for integrin signalling. In addition to cytosolic proteins, integrins most likely interact with proteins within the membrane resulting into new signalling modalities. In this proposal we will use innovative, modern and even unconventional techniques (such as RNAi and live-cell arrays detecting integrin traffic, cell motility and multiplication, laser-microdissection, proteomics and bacterial-two-hybrid screens) to unravel these new integrin functions, for which we have preliminary evidence. Each project will give fundamentally novel mechanistic insight into the role of integrins in cancer. Moreover, these interdisciplinary new openings will increase our understanding in cancer progression in general and will open new possibilities for therapeutic intervention targeting both cancer proliferation and dissemination in the body.
Max ERC Funding
1 529 369 €
Duration
Start date: 2008-08-01, End date: 2013-07-31
Project acronym NUCLEARACTIN
Project Actin as the Master Organizer of Nuclear Structure and Function
Researcher (PI) Maria Kristina Vartiainen
Host Institution (HI) HELSINGIN YLIOPISTO
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary Unlike previously thought the nucleus is a highly compartmentalized organelle. Both the genome and processes associated with it show non-random distribution within the nucleus. This compartmentalization has a fundamental impact on nuclear processes. However, the mechanisms driving this organization are poorly understood. I hypothesize that actin plays a key role in this process. Nevertheless, the true potential of nuclear actin has not been fully appreciated, due to two fundamental open questions in this field, namely 1) what is the biological significance of nuclear actin and 2) what is the molecular mechanism by which actin operates in the nucleus? I intend to address these key questions by manipulating actin specifically in the nucleus, and by identifying nuclear actin binding partners, respectively. My lab has recently identified the nuclear import mechanism for actin, which offers us a unique tool to manipulate nuclear actin. We will therefore create cell lines with decreased/increased nuclear actin, and analyze the consequences by using cell biological and gene expression tools, combined with deep sequencing. This will disclose the genes that depend on actin for their expression, and reveal the biological significance of nuclear actin in organizing the general nuclear landscape. To unravel the mechanisms by which actin functions in the nucleus, we will implement a novel multi-readout, fluorescence microscopy screen to identify nuclear actin binding proteins, which will be analyzed by different biochemical methods. This approach will reveal how actin is connected to nuclear machineries, and what biochemical features of actin are required to power the essential nuclear processes. These techniques will significantly broaden our understanding on the nuclear functions of actin, and thus likely reveal molecular mechanisms that regulate nuclear organization, which are highly relevant to basic biological processes, such as cell differentiation and epigenetics.
Summary
Unlike previously thought the nucleus is a highly compartmentalized organelle. Both the genome and processes associated with it show non-random distribution within the nucleus. This compartmentalization has a fundamental impact on nuclear processes. However, the mechanisms driving this organization are poorly understood. I hypothesize that actin plays a key role in this process. Nevertheless, the true potential of nuclear actin has not been fully appreciated, due to two fundamental open questions in this field, namely 1) what is the biological significance of nuclear actin and 2) what is the molecular mechanism by which actin operates in the nucleus? I intend to address these key questions by manipulating actin specifically in the nucleus, and by identifying nuclear actin binding partners, respectively. My lab has recently identified the nuclear import mechanism for actin, which offers us a unique tool to manipulate nuclear actin. We will therefore create cell lines with decreased/increased nuclear actin, and analyze the consequences by using cell biological and gene expression tools, combined with deep sequencing. This will disclose the genes that depend on actin for their expression, and reveal the biological significance of nuclear actin in organizing the general nuclear landscape. To unravel the mechanisms by which actin functions in the nucleus, we will implement a novel multi-readout, fluorescence microscopy screen to identify nuclear actin binding proteins, which will be analyzed by different biochemical methods. This approach will reveal how actin is connected to nuclear machineries, and what biochemical features of actin are required to power the essential nuclear processes. These techniques will significantly broaden our understanding on the nuclear functions of actin, and thus likely reveal molecular mechanisms that regulate nuclear organization, which are highly relevant to basic biological processes, such as cell differentiation and epigenetics.
Max ERC Funding
1 491 484 €
Duration
Start date: 2012-11-01, End date: 2018-08-31
