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The Wicked Cell
Integrating the Signals of alphavbeta3 Integrin
Saint Joan Antida SMART Team: Beanca Buie, Brianna Castanon, Neli Jasso, Alexis LockettGlover, Shinny Vang, Fatima Yacoob, and Sukaina Yacoob
Advisor: Cindy McLinn
Mentors: Emily Andreae and Sally Twining, Ph.D., Medical College of Wisconsin
Abstract
In order for a cell to interact and adapt to its environment, the cell needs receptors to recognize and respond to external signals. These signals tell a cell to migrate, proliferate, or specialize. Without receptors, a
cell would be unable to function within its environment. One group of receptors that enable a cell to interact with its environment are the integrins. There are several families of integrins, one of which is the β3
family. Cyr61, a protein associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis, is an activation-dependent ligand of the β3 integrin family. This group of
adhesive receptors mediates cell-cell and cell-extracellular matrix interactions. One of the two family members is αvβ3, an integrin expressed on the surfaces of endothelial cells, smooth muscle cells, monocytes,
platelets, and osteoclasts. Binding of Cyr61 to αvβ3 stimulates angiogenesis, the creation of blood vessels, and migration of tumor cells.
αvβ3 integrin commonly binds to the amino acid sequence RGD (arginine, glycine, and aspartic acid) on many extracellular molecules such as vitronectin and fibronectin, however, Cyr61 binds to αvβ3 via a unique
sequence. When a ligand binds to αvβ3 integrin, a conformational change in αvβ3 initiates a signaling cascade that results in increased cell migration. Over-expression of αvβ3 can lead to life-threatening cancers
such as breast cancer, melanoma, and colon cancer. Understanding and finding a way to restrict the expression and activation of αvβ3 integrin may lead to a new treatment of tumors with decreased side effects
compared to conventional chemotherapy.
Potential targets against αVß3 on cancer cells
Introduction
Conventional chemotherapy is a common
treatment for cancer, but it still has many
flaws and side-effects. Chemotherapy is
designed to destroy fast-growing cancer
cells, but unfortunately, the drug also attacks
other rapidly-growing cells such as hair and
blood cells. In addition, some cancer cells
grow slowly; therefore, the drug may not
detect the cancer. One potential treatment
that scientists are working on is blocking the
binding of an angiogenesis-inducing protein,
Cyr61, to an integrin, αvβ3. αvβ3 is expressed
in blood vessel cells, and plays a role in
angiogenesis (the growth of blood vessels).
When the two proteins (Cyr61 and αVß3)
bind, it causes a cascade of signals to
create more blood vessels, which enhances
tumor growth. Blocking the binding of these
two proteins could potentially be an
alternative to conventional chemotherapy.
1l5g.pdb
Synthetic Peptide Reactions
Figure A
Binding of Cyr61 to αvβ3 stimulates angiogenesis, the
creation of blood vessels, and tumor cells. When the binding
occurs a change in αvβ3 creates a cascade of signals that
can lead to life-threatening cancers such as breast cancer
and melanoma. The image above illustrates potential ways
to block the function or expression of αvβ3 on cancer cells.
Conclusion
The connection between RGD & Cyr61
RGD (arginine, glycine, and aspartic acid)
•RGD is the binding site of αvβ3
Cyr61
• Plays a role in regulating cell survival or
apoptosis
• A 20-residue sequence in domain II of Cyr61
binds to αvβ3
• Pro-angiogenic
• Plays a role in wound healing and cancer cell
migration
• Cyr61 mutated at D125 in the vWF domain is
hindered in binding to αvβ3
SMART Teams are supported by the National Institutes of Health (NIH)National Center for Research Resources-Science Education Partnership Award
(NCRR-SEPA), and an NIH CTSA Award to the Medical College of Wisconsin.
Figure B
Creating an artificial peptide sequence or small molecular
inhibitor to prevent the binding of Cyr61 to αvβ3 is potentially
beneficial to treating cancerous tumors. The artificial peptide
sequence would bind to αvβ3 and block the process of
angiogenesis, cutting off the tumor’s ‘food’ supply causing
the tumor to disintegrate. This could lead to a potential
treatment with less side effects compared to conventional
chemotherapy.
Citations
Cyr61 (CCN1) and synthetic peptides V1-V4 which correspond to domains 1-4 of Cyr61 were
used to coat tissue culture plates (see graph above). BSA (Bovine Serum Albumin) is used as a
control. Human umbilical vascular endothelial cells (HUVECs) were added to the culture wells
and allowed to adhere for 30 minutes. The degree of adhesion was measured by methylene
blue staining. The cells bound to Cyr61 (CCN1) and V2. This is because V2 supports binding to
αVß3 (as shown in Figure A). In Figure B, where BSA does not bind to the synthetic peptides,
there is not a reaction (V1, V3, and V4). We can use this data to create a potential cancer
preventing drug.
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