www.med.uoc.gr Department  of  Biochemistry - Division of Basic Sciences - University  of  Crete
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Papakonstanti Evangelia

Ast Professor of Biochemistry, Department of Biochemistry
Faculty of Medicine, University of Crete

Research Directions

This laboratory is investigating the molecular mechanisms underlying directional cell migration and cell survival with a particular focus on cancer cell growth, metastasis and inflammation. Currently, we are focusing on the pathways regulated by Rho GTPases and PI3 kinase-isoforms.

Our goal is to understand the mechanisms that regulate tumour growth and metastasis aiming to gain important information for the development of promising drugs targeting specific molecules and cell functions.

Research Directions

Cell motility is one of the defining characteristics of invasive tumours enabling tumours to migrate into neighbouring tissues or to transmigrate limiting basement membranes and extracellular matrices. The invasive process is enhanced by chemotaxis (directional migration) of cancer cells towards extracellular signals which most often are growth factors. Tumour cells and macrophages migrate toward each other in response to EGF (produced by macrophages) and CSF-1 (produced by cancer cells) and through this paracrine pathway macrophages promote the invasion of breast cancer cells. Additionally, macrophages are recruited to sites of inflammation inducing matrix remodelling, angiogenesis and stimulation of tumour growth.

Research Directions

Phosphatidylinositol-3 kinases (PI3Ks) consist of a group of enzymes that produce PI(3,4,5)P3 which transmits signals inside cells regulating many important cellular functions including survival, growth and motility. Downstream of tyrosine kinases PI(3,4,5)P3 is produced by the class IA subset of PI3Ks. These are heterodimers made up of a 110 kDa catalytic subunit (p110a, p110b and p110d) in complex with one of 5 regulatory subunits (the 'p85s'). Downstream of GPCRs, PI(3,4,5)P3 is produced by the class IB PI3K (p110g) which binds to a p101/p87. All class I PI3Ks signal downstream of Ras. Deregulated PI3K signalling because of either activation of oncogenes or inactivation of tumour suppressors is implicated in cancer progression.
A feature of many common cancers is the misregulation of PI(3,4,5)P3 production often because of reduced or lost activity of the main antagonist of PI3K, the PTEN tumour suppressor protein. PTEN degrades the PI(3,4,5)P3 produced by PI3Ks, thus controlling cell proliferation and survival. Reduced activity or inactivation of PTEN creates a state in which PI3K is constitutively active leading to abnormal cell growth.

As the PI3K pathway is important for many normal cellular functions its global inhibition is associated with severe toxic effects and could be deleterious for the organism. Therefore, it is critical to understand the roles of the PI3K isoforms.

Research Directions
Research Directions

The activity of Rho GTPases is controlled by positive and negative regulators. Rho proteins are activated by guanine nucleotide exchange factors (GEFs) whereas the return from their active state to an inactive state is catalyzed by the GTPase-activating proteins (GAPs). The activation of Rho GTPases is prevented by the guanine nucleotide dissociation inhibitors (GDIs).

Directional sensing and migration requires PI(3,4,5)P3 accumulation at the leading edge and cyclic activation-inactivation of the Rho GTPases for cell body to move properly.


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