Kathleen A. Gallo Research Interests
Protein phosphorylation is a dynamic
and reversible event essential to the proper functioning of physiological
processes, including cell proliferation and programmed cell death. Because
protein phosphorylation is a regulatory event, it follows that the protein
kinases that catalyze phosphorylation, should themselves be subject to regulation.
The improper regulation of protein kinases has been implicated in many human
pathologies, including cancer. The overall goal of the Gallo Laboratory
is to understand the molecular basis by which protein kinases and their
signaling pathways are regulated in normal cells and in cancer.
The mixed-lineage kinases (MLKs) are a family of serine/threonine kinases
that function as mitogen-activated protein kinase kinase kinases (MKKKs)
to activate the JNK pathway. In some experimental settings, the MLKs may
also activate the ERK, p38 MAPK and nuclear factor Kappa B (NF-kappa B)
pathways. The MLKs have garnered attention as important mediators of apoptosis,
particularly in neuronal cells.
Our lab
is using MLK3 as a paradigm to study the mixed lineage family of protein
kinases. MLK3 contains several potential protein-protein interactions domains
that likely contribute to its regulation and signaling specificity, including
an N-terminal SH3 domain, a centrally located zipper and a Cdc42/Rac Interactive
Binding (CRIB) motif, and a C-terminal region with a preponderance of serine,
threonine, and proline residues. Work in our lab indicates that MLK3 is
autoinhibited through an interaction between its SH3 domain and a noncanonical
SH3 binding motif that is situated between the zipper and CRIB motifs. We
have also found that activated forms of the small GTPases Cdc42 and Rac
increase MLK3's autophosphorylation and substrate phosphorylation activity,
change the subcellular localization of MLK3, and are correlated with changes
in MLK3's in vivo phosphorylation status.
The Gallo Laboratory uses biochemical, biophysical and cell biological approaches-including
confocal microscopy and mass spectrometry- towards understanding the molecular
mechanisms that regulate MLKs and their signaling pathways. Areas of particular
interest are described below.