Vitamin K—dependent proteins (VKDPs) in tissue homeostasis
- Principle investigator:
- Pablo García de Frutos / Gines Escolar
- Contact details:
We are interested in vitamin K-dependent proteins (VKDPs). VKDPs are calcium and membrane binding extracellular proteins with two important characteristics. First, they are able to interact in a calcium dependent manner with negatively charged-phosphatidyl serine-containing membranes, as in activated endothelium or platelets, and in the initial phases of apoptosis. Second, they interact with membrane receptors, acting as ligands in processes of response to damage. The best well-known VKDPs are those of the coagulation cascade, as prothrombin. Oral anticoagulants affect vitamin K action, inhibiting coagulation but, collaterally, all other VKDPs.
We are particularly interested in two genes of this family, GAS6 and PROS1. These genes produce proteins that are able to interact with activated membranes through the N-terminal domain and with specific tyrosine kinase receptors through the C-terminal part, acting as growth-factor like molecules. Through these actions, they play key roles in cellular homeostasis and tissue repair, and regulate immunity. Gas6 and ProS exert their function through the TAM receptor tyrosine kinases, a subfamily of RTKs composed of Tyro3, Axl and MerTK.
We have addressed the study of the biology of these proteins by using genetic models of pathology in mice. Characterization of GAS6 deficient mice led us to the discovery of regulatory mechanisms in hemostasis (Nat Med 2001), inflammation (Blood 2008) and atherosclerosis (J Pathol 2008). Recently, in we collaborated in the discovery of a vitamin K-dependent mechanism in adult neurogenesis (Stem Cells 2012). We are focusing our research in the role of these proteins in tissue repair after damage, and specifically in adult stem cell survival and activation in pathological situations related to intestinal inflammatory diseases and cancer.
Our group has a long experience studying the biology of VKDPs, started in 1994 with the discovery of the basis of certain forms of hereditary venous thrombosis (Blood 1994, Blood 1995a, 1995b, Ann Int Med 1998). We have been characterizing the mouse knockout of Gas6 deficiency for more than a decade and collaborate with laboratories from USA and around Europe interested in this protein.
Vitamin K-dependent proteins, Adult stem cells, Tissue repair, receptor tyrosine kinases, animal models
Tissue repair after damage is a crucial step in the recovery of functional organs challenged by a disease. To find specific mechanisms of repair for adult tissues could provide new pharmacological targets. There is a connection of the responses to damage (inflammation) and the development of certain forms of cancer, as inflammation-driven cellular proliferation is known to be the cause of certain types of malignancies.
We have found that GAS6 deficiency causes a marked impairment of tissue regeneration in mouse models of colon ulceration. We now plan to further investigate the role of GAS6 in the proliferation associated to inflammation that is the basis of malignant growth in colitis-associated cancer (CAC).
This project will provide evidence that activation of the GAS6/ProS-TAM may prevent intestinal cell proliferation evoked by chronic inflammation. It will also generate the necessary tools for detecting components of this system in biologically relevant samples for diagnostic purposes. In this way, we expect that the project could lead to obtaining transferable technology for the industrial sector.
Team strategic objective in IDIBAPS
Our strategic objective is to study the biology of Gas6 and ProS VKDPs in hemostasis and the vascular wall, using knockout mice for these genes. Besides, we are interested in understanding the role of these genes in the mechanisms of response to damage.(Read eligibility criteria)