Welcome to Habas Lab!
Research Fields
Signal
Transduction, Biochemistry, Gene Expression, Cell Biology, Developmental
Biology and Cancer Biology
Research Description
My
laboratory is focused on understanding the role of the Wnt signaling pathway
during embryogenesis and tumorigenesis.
Understanding
the development of an organism from a fertilized egg into a multi-cellular
organism with proper polarity including dorso-ventral, anterior-posterior and
left-right symmetry remains a challenge for biologists. This embryological
process is tightly regulated temporally and spatially and results from
interplay between several signaling pathways, and one key signaling pathway
required is the Wnt pathway. Wnt signaling has been demonstrated to regulate
critical cell fate determination, proliferation, behavior, adhesion, migration
and polarity during development. Wnt and its signaling components, in addition
to playing a crucial role in embryogenesis have been implicated in
tumorigenesis and play causative roles in human colon cancers.
We are
dissecting the Wnt signaling pathway using a multidisciplinary approach drawing
on techniques from molecular biology, biochemistry, cell biology and
embryology. Our primary system is the Xenopus
laevis (frog) and mammalian culture cells.
The Wnt signaling cascade has evolved as a complex series of independent signaling modules and to date comprises of three signaling modules; a canonical, a non-canonical and a Wnt/Ca2+ pathway. The canonical pathway regulates cell fate determination and primary axis formation through gene transcription, the non-canonical pathway regulates cell movements through modification of the actin cytoskeleton and the Wnt/Ca2+ pathway impacts both cell movements and cell fate determination.
We are focusing on studies to define the molecular
basis of Wnt signaling by analyzing the role of Dishevelled (Dvl), a key
component. For canonical signaling, we described the individual amino acid
residues required for the binding of Axin, an important negative regulator of
canonical Wnt signaling, to Dvl. We further deciphered the individual amino
acids that were required for the targeting of Dvl to vesicles and were required
for canonical pathway activation; this work represented a collaborative study
with the Overduin group at the University of Colorado. For non-canonical
signaling, we demonstrated that the small GTPase Rho can be biochemically
activated by a Wnt/Fz/Dvl cascade in mammalian cells and Xenopus embryos, and we identified a novel effector for Rho
activation downstream of Dvl. This protein, Daam1, is a member of the formin
family of cytoskeletal proteins, and we showed that Daam1 has a critical role
in mediating gastrulation cell movements. We further demonstrated that the Rac
GTPase could also be biochemically activated by a Wnt/Fz/Dvl cascade, and that
Jun kinase functions downstream of Rac in this pathway. This Rac/Jun kinase pathway
was activated independently of Daam1/Rho activation, leading us to propose that
the activation of Rho and Rac were independent and parallel signaling pathways
required for gastrulation cell movements. Together, these studies have
deciphered the contributions of individual domains of Dvl in transducing Wnt
signaling. We demonstrated a pathway similar to the Planar Cell Polarity
pathway of Drosophila for the regulation of gastrulation and defined
biochemical pathways for the regulation of cell polarity and gastrulation
movements by Wnt signaling. Our demonstration of the roles of Rho and Rac as
mediating effects of Wnt signaling on the cytoskeleton may provide an important
avenue for the understanding of aspects of Wnt-mediated tumorigenesis.
We are
now continuing our studies by analyzing a number of new factors that we have
identified that impact the canonical or the non-canonical pathways. These
studies will provide a clearer understanding of the mechanisms of Wnt signaling
and remains pivotal to our understanding of the molecular nature of embryology
and cancer formation.
RM629, Resarch Tower
627 Hoes Lane, Piscataway, New Jersey, 08854
Lab Phone: (732) 235-4193