SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
also are involved in cell migration, patterning of
the nervous system, and angiogenesis. Given their
critical roles in neuronal regeneration and angiogenesis,
ephrins and their receptors are excellent
targets for therapeutic intervention in a variety of
cancers, injuries, and diseases.
Eph receptors are the largest-known family
of receptor tyrosine kinases, with at least 16
members identified until now. Eph receptors have
an extracellular region that consists of two
fibronectin motifs, a cysteine-rich region, and a
conserved 180 amino acids N-terminal globular
domain. The ligands for Eph receptors are the
ephrins, which have eight members identified so
far. These ligands share conserved core sequences
of approximately 125 amino acids, including four
invariant cysteine residues. Ephrin A1–A5 are
anchored by glycosil-phosphatidil-inositol (GPI)
to cellular membranes, while ephrin B1–B3 receptors
have a transmembrane domain and an
intracellular domain, which interacts with a variety
of adapter and signaling molecules such as
PDZ-RGS3, GRB4, JNK, and others.
The two classes of ephrins and their receptors,
A and B, are defined by sequence homologies,
mechanism of membrane anchorage, and by preferential
binding of the ligands to their receptors.
While within the same class, the ligand-receptor
binding tends to be nonspecific; there is no cross
interaction between the two classes, except Eph
A4, which binds some of the B class ephrins.
Ephrins-Eph interactions also are intriguing because
these molecules often display bidirectional
signaling: a forward signal (binding of ephrins to
Eph receptor determines a response in a cell or
axon) and a reverse/downstream signal (binding
of Eph receptor to ephrin causes a change in the
cell or axon to which ephrin molecule is bound).
This research aims to better understand the
structural basis of ephrin/Eph ligand-receptor binding
and specificity by crystallographic studies of
the extracellular domains of several of these molecules.
Residues identified as being critical for ephrin/
Eph specificity also will be tested functionally using
mutational approaches, in collaboration with the
laboratory of Daniel J. Leibl, Ph.D., at The Miami
Project to Cure Paralysis, University of Miami.
88
SELECTED PUBLICATIONS
2003
Everhart, D, Reiller, E, Mirzoian, A, McIntosh,
JM, Malhotra, A, and Luetje, CW. Identification
of residues that confer a-conotoxin-PnIA sensitivity
on the α3 subunit of neuronal nicotinic acetylcholine
receptors. Journal of Pharmacology
and Experimental Therapeutics 306: 664-70,
2003.
Del Campo, M, Ofengand, J, and Malhotra, A.
Purification and crystallization of Escherichia coli
pseudouridine synthase RluD. Acta
Crystallographica D, 59:1871-73, 2003.
Del Campo, M, Ofengand, J, and Malhotra, A.
Crystal structure of the catalytic domain of
RluD, the only rRNA pseudouridine synthase
required for normal growth of Escherichia coli.
RNA 10:231-39, 2003.
AKILA MAYEDA, PH.D.
Assistant Professor of Biochemistry
and Molecular Biology
DESCRIPTION OF RESEARCH
The human genome project has underscored
the critical importance of alternative premRNA
splicing for expressing a full proteome
with its complexity from an unexpectedly small
set of genes, i.e., less than 30,000 by most recent
estimation.
Researchers in Dr. Mayeda’s laboratory are
working to understand the basic mechanisms of
splicing regulation in human genes. Three main
projects are ongoing: 1) to study the function of
the human splicing activator RNPS1, which is
also an important factor to link splicing and the
post-splicing process, e.g., nonsense-mediated
mRNA decay (NMD); 2) to study the function
of human HMGA1a, which is the hypoxia-inducible
factor causing aberrant splicing of
Presenilin-2 (PS2) pre-mRNA. PS2 is one of the
genes linked to Alzheimer’s disease (AD); and
3) to study the splicing mechanisms of extremely
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004