|
Faculty Linda Shapiro
Associate Professor of Cell Biology
Program Director, Graduate Program in Cell Biology
lshapiro@neuron.uchc.edu
Areas of Interest:
Our laboratory has concentrated on
understanding the regulation and function of the CD13/APN cell surface
peptidase in hematopoietic cells and more recently, in angiogenic
endothelium of tumors and cardiovascular disease. CD13/APN is found on a
wide spectrum of human tissues and since it is an extracellular
peptidase, its function in a particular tissue depends on the functional
substrates that are available in the extracellular space. For example,
in the brain CD13/APN cleaves opioid peptides and enkephalins to
regulate their function. Therefore, studying its function in a
particular tissue may provide clues to the identity of relevant
regulatory peptide substrate(s). We have shown that inhibition of CD13/APN
can block endothelial morphogenesis and invasion and a major focus of
the lab is to examine the molecular mechanisms responsible for its
angiogenic regulatory capabilities, particularly its role in invasion.
In this regard, we have expanded our studies into tumor cells where
CD13/APN expression correlates with the cell’s ability to invade. We
have identified a subset of breast tumor cells whose invasion is
particularly dependent on CD13/APN and are focusing on identifying
auxiliary molecules that collaborate with CD13/APN in invasion. Since
CD13/APN is expressed on angiogenic but not normal endothelial cells, it
is also a useful model to investigate signal transduction and
transcriptional mechanisms controlling expression of angiogenic
regulatory molecules and may provide clues to the molecular basis of
vascular heterogeneity. In this regard, we are also studying CD13/APN
induction by inflammatory signals which are primarily responsible for
angiogenesis in response to ischemia in myocardial infarction. We have
seen that CD13/APN protein levels are highly induced in ischemic
myocardium and have identified a soluble factor produced by cells of the
myeloid lineage that potently induces CD13/APN transcription in
endothelial cells. In addition, like CD13/APN, certain other cell
surface peptidases are upregulated in angiogenic endothelium, suggesting
their participation in this process as well. We are currently
investigating the upregulation and function of glutamyl-carboxypeptidase
II in endothelial cells and its possible functional cooperation with
CD13/APN in angiogenesis and endothelial cell function. Finally, the
lineage specific expression of CD13/APN in the hematopoietic lineage
allows us to study transcriptional mechanisms that might dictate lineage
choice during hematopoietic development and provide insights into the
transcriptional regulation of cell fate decisions.
Lab Rotation Projects:
Role of cell surface peptidases in endothelial invasion.
Selected Publications:
Petrovic N, Schacke W, and Shapiro LH, CD13/aminopeptidase N in Tumor
Growth & Angiogenesis. In: Hooper and Landeckel Ed. Aminopeptidases in
Biology and Disease. Kluwer Academic/Plenum Publishers pp. 179-200,
2004.
Bhagwat SV, Petrovic, N, Okamoto Y, and Shapiro LH. The angiogenic
regulator CD13/APN is a transcriptional target of Ras signaling pathways
in endothelial morphogenesis Blood 101:1818-1826, 2003.
Petrovic N, Bhagwat SV, Ratzan WJ, Ostrowski MC, and Shapiro LH,
CD13/APN Transcription is Induced by Ras/MapK Mediated Phosphorylation
of Ets-2 in Activated Endothelial Cells, J. Biol Chem 278:49358, 2003.
Bhagwat SV, Okamoto Y, and Shapiro LH, CD13/APN as a Target for
Inhibiting Tumor Angiogenesis: A Molecular Basis for the Differential
Expression of CD13/APN in Vascular Endothelium. In: Langner and Ansorge
Ed. Ectopeptidases. Kluwer Academic/Plenum Publishers pp 123-140, 2002.
Bhagwat SV, Lahdenranta J, Giordano R, Arap W, Pasqualini R, and
Shapiro LH. CD13/APN is activated by angiogenic signals and is essential
for capillary tube formation. Blood, 97:652-659, 2001.
Pasqualini R, Koivunen E, Kain R, Lahdenranta J. Sakamoto M, Stryn A,
Ashmun, RA, Shapiro LH, Arap W, and Ruoslahti E. Aminopeptidase N is a
receptor for tumor-homing peptides and a target for inhibiting
angiogenesis. Cancer Research, 60:722-727, 2000. |
