Project Number: T32 CA 106195
Project Title: TRAINING IN MOLECULAR BASIS OF SKIN PATHOBIOLOGY
Institution: OREGON HEALTH & SCIENCE UNIVERSITY
PD Name: KULESZ-MARTIN, MOLLY F.
QUENTIN E. LOW, PhD
Dr. Low trained in the lab of Dr. Philip Stork, MD (Vollum Institute, Oregon Health &
Science University) during his appointment to this program. He studied activating
mutations in signaling pathways that often lead to uncontrolled cell proliferation. The
extracellular signal regulated kinase (ERK) pathway controls a large range of cellular
functions, ranging from cell proliferation to differentiation and cell death. B-Raf is a
serine/threonine kinase within the pathway and is mutated in 60% of human melanomas.
Many of the identified mutations led to enhance kinase activity, of which 95% of those
mutations are localized within the catalytic domain of B-Raf. While B-Raf shares many
similarities with two other isoforms, A-Raf and Raf-1, B-Raf is unique in its involvement
in human pathology. B-Raf also contains an amino terminal extension that is not found
in other members of the Raf kinase family. The role of this 100 amino acid extension in
both B-Raf biology and pathology is not known. To address the requirements of this
extension in B-Raf signaling, he helped to create amino-terminal truncation mutants, and
assay for this mutant's ability to perform established B-Raf functions, such as responding
to cell stimulation by growth factor addition or cAMP elevation, being in a complex with
scaffolding proteins, KSR and 14-3-3; dimer formation with itself and activation of
downstream targets, ERKs. He found that the truncation mutant did not display any
impairment in the cells' ability to respond to growth factor simulation, complex with
KSR, form homodimers or to activate ERKs. However, the B-Raf amino-terminal
truncation mutant did show enhanced association with 14-3-3 and had reduced
phosphorylation on cAMP responsive residues. These preliminary findings suggest that
the amino terminus of B-Raf may play a role in regulating its responses to cAMP
signaling. This idea is consistent with published observations that B-Raf is activated via
cAMP-dependent pathways and the control of B-Raf signaling specificity by 14-3-3.
Dr. Low gave a talk on wound healing at a Department of Dermatology's Translational
Topics meeting of clinical and research faculty. He also presented on his work to the
Dermatology research division joint lab meeting, and spoke at the OHSU Signal
Transduction journal club.