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PEA-15 and its Association
with Diabetes and Cancer
Jade Buchanan-Carter
Aaron Buechlein
Leo Senderowicz
School of Informatics
© 2006 Bioinformatics
Indiana University
April, 24th 2006
1
Outline
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Introduction
Background and Motivation
Association to Disease
Potential for Drug Therapy
Catpa
Summary
© 2006 Bioinformatics
Indiana University
April, 24th 2006
2
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
Introduction
• Phosphoprotein enriched in astrocytes 15
• Located on Chromosome 1 specifically at 1q21.1
• Originally identified by Chneiweiss and colleagues.
• Most highly expressed in the nervous system
• Particularly high levels in astrocytes and
neurons of the hippocampus
© 2006 Bioinformatics
Indiana University
April, 24th 2006
3
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
© 2006 Bioinformatics
Indiana University
April, 24th 2006
4
> Introduction
What are Astrocytes?
> Background
&
Motivation
• Astrocytes are the most common type of glial cells in the
nervous system
> Disease
Association
• They have numerous projections that anchor neurons to
their blood supply.
> Therapeutic
Agent
> Catpa
> Summary
• They regulate the external chemical environment of
neurons by removing excess ions, notably potassium, and
recycling neurotransmitters released during synaptic
transmission.
• Actually outnumber neurons ten to one.
© 2006 Bioinformatics
Indiana University
April, 24th 2006
5
> Introduction
> Background
&
Motivation
Scop Classification
> Disease
Association
> Therapeutic
Agent
> Catpa
> Summary
Class: All Alpha
Fold: DEATH domain
Superfamily: DEATH domain
Family: DEATH effector domain
© 2006 Bioinformatics
Indiana University
April, 24th 2006
6
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Catpa
> Summary
Death Effector Domain
• Part of the Death effector Domain (DED) protein
family which is generally associated with regulation of
apoptosis.
• CASP8
• FADD
• CFLAR
• Caspase 10
• DEDD
• DEDD2
© 2006 Bioinformatics
Indiana University
April, 24th 2006
7
Binding
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
• PEA15 contains two phosphorylation sites.
• Ser104 and Ser116
• Ser116 is phosphorylated by calcium-calmodulin kinase
II and also by Akt (protein kinase B)
• Ser104 is phosphorylated by protein kinase C
• PEA15 is reported to bind FADD via its death domain,
blocking its ability to recruit caspases thus preventing
cell death.
• PEA15 is also reported to bind ERK1/2, a MAP kinase,
retaining ERK in the cytoplasm.
© 2006 Bioinformatics
Indiana University
April, 24th 2006
8
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
PEA-15 Phosphorylation
• Unphosphorylated PEA15 is reported to be
apoptotic, but the phosphorylated form is
believed to be antiapoptotic.
> Pathway
> Catpa
> Summary
• Phosphorylated at both Ser104 & 116, PEA15
blocks its interaction with ERK1/2
• Phosphorylated at Ser104, PEA15 blocks ERK
binding
• Phosphorylated at Ser116, PEA15 promotes
FADD binding.
© 2006 Bioinformatics
Indiana University
April, 24th 2006
9
> Introduction
> Background
&
Motivation
Disease Association
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
• Type II Diabetes
• Over expression of PEA15 has been found to inhibit
insulin-stimulated glucose transport.
• Cancer
• Found to be overexpressed in cell lines associated with
Breast Cancer, Glioma, and Squamous Carcinoma.
• Hypothesized to prevent cellular apoptosis and/or
promote cell proliferation.
© 2006 Bioinformatics
Indiana University
April, 24th 2006
10
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
Clinical Background of Diabetes
• Previously called non–insulin-dependent
diabetes mellitus (NIDDM) or adult-onset
diabetes.
• Accounts for about 90% to 95% of all
diagnosed cases of diabetes.
• Associated with older age, obesity, family
history of diabetes, history of gestational
diabetes, impaired glucose metabolism,
physical inactivity, and race/ethnicity.
• In type 2 diabetes, not enough insulin
produced or body ignores insulin action
© 2006 Bioinformatics
Indiana University
April, 24th 2006
11
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
Diabetes type II study
• Overexpression of the ped/pea-15 gene causes
diabetes by impairing glucose-stimulated insulin
secretion in addition to insulin action.
• Overexpression of the ped/pea-15 gene is a
common feature of type 2 diabetes.
• Stable overexpression of ped/pea-15 in the
glucose-responsive MIN6 beta-cell line also
caused protein kinase Calpha activation and a
marked decline in glucose-stimulated insulin
secretion.
• Antisense block of endogenous ped/pea-15
increased glucose sensitivity by 2.5-fold in these
cells
• Cells rescued by the protein kinase C inhibitor
bisindolylmaleimide (Ser104).
© 2006 Bioinformatics
Indiana University
April, 24th 2006
12
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
PEA15 associated cancers
• A glioma is a type of primary central nervous system
(CNS) tumor that rises from glial cells.
• Squamous Cell Carcinoma: affects tissues such as
skin, the esophagus, the lungs, and the cervix.
- 200,000 people in the United States alone every
year. Smoking is a significant risk factor.
• Breast Cancer
- Most common form of cancer in females
(worldwide) - affects one out of eleven women in
the western world.
- genetic factors (i.e. DNA damage of
BRCA1,BRCA2) and environmental factors
(alcohol, birth control pills).
© 2006 Bioinformatics
Indiana University
April, 24th 2006
13
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
Therapeutic Agent(s)
• Dominant negative expression of AKT increases apoptosis
in vitro
• Thus, promoting apoptosis via inhibition of AKT
phosphorylation can be used as drug therapy
• Targeting the PI3K(phosphoinositol-3-kinase) pathway is the
strategy available in literature
• LA (leuprolide acetate) inhibits phophorylation of AKT which
leads to inhibition of phosphorylation on Ser116 of PEA15
which increases apoptosis
• Rapamycin also targets PI3K pathway and slows down
tumor growth without significant side effects in animal
models
Healthy
© 2006 Bioinformatics
Unhealthy
Indiana University
April, 24th 2006
14
> Introduction
> Background
&
Motivation
Omi/HtrA2
Phosphorylation at
Ser-104 by PKC
> Disease
Association
> Therapeutic
Agent
Phosphorylation
at Ser-116 by
CaKII or Akt
Anti-Apoptotic
Activity
Increase in
cell surface
Glut1
PEA-15
Overexpression
Inhibits glucose
transport due to
impairment of
insulin-dependent
Glut4
> Pathway
FADD
> Catpa
ERK
> Summary
Elk1
Fas
Type 2 Diabetes mellitus
CELL PROLIFERATION
Caspase 8/10
CREB mediated
transcription
APOPTOSI
S
© 2006 Bioinformatics
Indiana University
April, 24th 2006
15
> Introduction
> Background
&
Motivation
Curation Alignment Tool for Protein
Analysis
> Disease
Association
> Therapeutic
Agent
> Pathway
CATPA DATA??
> Catpa
> Summary
CATPA
© 2006 Bioinformatics
Indiana University
April, 24th 2006
16
Summary
> Introduction
> Background
&
Motivation
> Disease
Association
> Therapeutic
Agent
> Pathway
> Catpa
> Summary
• Excess of PEA15 in cells reduces apoptosis and
promotes cell proliferation via binding to FADD
and ERK1/2 respectively
• Study of these pathways may lead to discovery of
therapeutic agents for treatment of cancer and
diabetes
© 2006 Bioinformatics
Indiana University
April, 24th 2006
17
Citations
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7.
Tibbetts, M., Zheng, L., Lenardo, M. The death effector domain protein
family: regulators of cellular homeostasis. Nature 4, 404-409 (2003).
Ramos, J.W., PEA-15 Phosphoprotein: A potential cancer drug target.
Hawaii Med. J. 64, 77-79 (2005).
Kitsberg, K. et al. Knock-Out of the neural death effector domain protein
PEA-15 demonstrates that its expression protects astrocytes from TNFαinduced apoptosis. The J. of Neuroscience 19, 8244-8251 (1999).
Underhill, D.A., Vogan, K.J., Underhill, T.M., Gros, P., Identification of a
novel, alternatively spliced isoform and single nucleotide polymorphisms
in the murine Pea-15 gene. Mammalian Genome 12, 172-174 (2001).
Renganathan, H., Vaidyanathan, H., Knapinska, A., Ramos, J.W.,
Phosphorylation of PEA-15 switches its binding specificity from
ERK/MAPK to FADD. Biochem. J. 390, 729-735 (2005).
Wolford, J.K., Bogardus, C., Ossowski, V., Prochazka, M., Molecular
characterization of the human PEA15 gene on 1q21-q22 and association
with type 2 diabetes mellitus in Pima Indians. Gene 241, 143-148 (2000).
Condorelli, G., Vigliotta, G., Iavarone, C., Caruso, M., Tocchetti, C.G.,
Andreozzi, F., Cafieri, A., Tecce, M.F., Formisano, P., Beguinot, L.,
Beguinot, F., PED/PEA-15 gene controls glucose transport and is
overexpressed in type 2 diabetes mellitus. The EMBO J. 17, 3858-3866
(1998).
© 2006 Bioinformatics
Indiana University
April, 24th 2006
18
Questions
© 2006 Bioinformatics
Indiana University
April, 24th 2006
19