Research

Research Interests
Our lab is interested in understanding of the molecular and cellular mechanisms that underlie tissue homeostasis in health and in disease. We investigate the role of TAM receptors and their agonists Protein S and Gas6 in development and throughout adulthood. We combine biochemical, cell- biological and genetically engineered mouse model approaches. Tyro3, Axl, and MerTK comprise the TAM family of receptor tyrosine kinases. Together with their ligands Gas6 and Protein S (PROS1) TAM signaling plays a key role in maintaining a healthy balance in various physiological systems, including the endothelial, nervous, immune and reproductive systems. Several human diseases are associated with the dysregulation of TAM signaling and its components, including blood hypercoagulation, inflammation, cancer, autoimmune disease and blindness. We focus on the role of PROS1 as a TAM ligand in various physiological settings, to understand how PROS1-mediated TAM signaling is critical to homeostatic regulation. Specific projects in the lab focus on the developing and adult nervous system, the vascular system and homeostatic maintenance in the eye. Several projects focus on PROS1 and TAMs in cancer.

Developmental focus of interest:

Protein S mediated TAM signaling in development:

Using advanced transgenic mouse models, we have showed that PROS1 is important for the
development of blood vessels and for their healthy function in adulthood (Burstyn-Cohen et al, JCI,
2009). We aim to learn more about the role of TAM signaling in the developing vasculature and the
developing nervous system, including processes which are developmental in nature but occur
postnatally.

Protein S mediated TAM signaling in adult homeostasis:

In the nervous system: Our lab has identified PROS1 as a multi-functional regulator of Neural Stem
Cell (NSC) biology. Expressed by both embryonic and adult NSCs, PROS1 is a major factor regulating
the balance between NCS proliferation versus quiescence (Zelentsova et al; Stem Cells, 2017) as well
as self-renewal versus differentiation (Zelentsova-Levytzkyi et al, Front Mol Neurosci 2017). PROS1
supports the neuronal cell fate over astrocytic differentiation, thus contributing to neurogenesis. We
continue to research the role of PROS1 in the nervous system, including in microglia.

In the eye: Mutations in MerTK lead to degeneration of photoreceptors, and consequent blindness in
mice, rats and humans. However, the basic mechanism by which TAM signaling functions is not yet
clear: what are the relevant ligand-receptor interactions? Which cells express them? In the lab, we aim to answer these questions in the eye, and to establish how PROS1 and TAM signaling are
important for a healthy retina.

In cancer: TAMs were identified as proto-oncogenes, and their overexpression and hyper-activation is
documented in many human cancers. However, which signals activate TAMs in cancers is not clearly
understood. We identified the overexpression of PROS1 in oral cancer, and revealed it supportive role
in tumor cell aggressiveness. In the same study, (Abboud-Jarrous et al, Oncotarget, 2017) we identified
a novel mechanistic mode of function for PROS1, by which PROS1 overexpression regulates AXL
expression levels, rather than binding and activating TAMs via the traditional ligand-receptor
interactions. We continue to study PROS1-mediated interventions in various cancers, including in
melanoma and the aggressive oral and lung carcinomas.

In the immune system: While TAMs are essential negative regulators of the immune system and key
inhibitors of inflammation, whether PROS1 regulates the various TAM roles in immune homeostasis
was not clearly understood until recently. We recently identified macrophages-expressed PROS1 plays
a role in the resolution of inflammation, by driving macrophage polarization and clearing dead
neutrophils from the site of inflammation (Lumbroso et al, Front Immunol, 2018). Our current research
is aimed at understanding how PROS1 regulates the immune response.
In collaboration with the Hovav lab in our institute, we investigate functional aspects of PROS1 and
GAS6 in oral immunity. Collaborative work has identified both TAM ligands as regulators of oral
immune homeostasis (Nassar et al, PNAS, 2017; Nassar et al, Front Immunol 2018; Tabib et al, PNAS
2018).