The goal of our research is to elucidate the role
of tyrosine kinases of the Abl family in the regulation
of normal development and pathological conditions
such as cancer, bacterial pathogenesis, muscular dystrophies,
neurodegenerative disorders, and immune deficiencies.
Through the study of Abl tyrosine kinases and associated
adaptors, we have gained novel insights on the regulation
of cell proliferation, survival, cell morphology,
migration, and synapse formation. We have shown that
the endogenous Abl kinases are activated by growth
factor receptors and function to link these receptors
to reorganization of the actin cytoskeleton. Abl kinases
are also activated by the Muscle Specific Tyrosine
Kinase (MuSK) on the postsynaptic side of the neuromuscular
junction (NMJ) in response to the nerve-derived organizing
factor agrin. Activation of the endogenous Abl family
kinases in muscle is required for the clustering of
Acetylcholine receptors (AChRs), which is essential
for muscle function. These results reveal a novel
role for Abl family kinases in synapse formation and
suggest that Abl kinases may modulate synapse formation
and/or maintenance in the central nervous system.
We are currently employing mouse models to define
the role of Abl kinases and their targets in cellular
processes ranging from synapse formation to learning
and memory.
More recently, we have begun to employ bacterial
pathogens as tools to dissect the mechanisms employed
by Abl kinases to regulate cytoskeletal dynamics.
We showed that endogenous Abl family kinases are required
for bacterial entry during Shigella flexneri infection.
Shigella is a gram-negative bacteria that causes dysentery
and affects over 160 million people per year around
the world, killing one million, mostly children. Shigellosis
is a severe threat as the regions most severely affected
by this disease present with antibiotic resistance.
We have discovered that pharmacological inhibition
of the Abl kinases blocks bacterial entry and phosphorylation
of normal Abl targets. We demonstrated that Abl kinases
are functionally linked to the Rac and Cdc42 GTPases
in a pathway initiated by Shigella entry into the
host cell. Our findings reveal a new role for Abl
family kinases in bacterial pathogenesis and suggest
a novel approach to the treatment of Shigellosis through
inhibition of host cell signaling pathways.
