The Mitogen Activated Protein Kinase/ Extracellular signal Regulated Kinase (MAPK/ERK) cascade controls cell growth and survival and adhesion. I have used an expression-cloning strategy to isolate a protein that blocks ERK/MAPK (p42/p44) signaling, PEA-15. PEA-15 impairs several ERK functions such as activation of transcription. PEA-15 binds directly to ERK1/2 and co-localizes with it in the cytoplasm. While PEA-15 contains a death effector domain (DED) it affects apoptosis (programmed cell death) in only a subset of cell types, specifically some fibroblasts and astrocytes. In the PEA-15 null mouse, the most striking phenotype is a lymphoproliferative syndrome affecting both B and T cells. There is also a marked increase in hepatocyte proliferation and atrophy of the epidermis. PEA-15 maps to human chromosome 1q21. This is a gene rich locus implicated in a number of diseases, including acute myeloblastic leukemia and the skin disorder Ichthyosis vulgaris. PEA-15 has been cloned as a gene upregulated in patients with type II diabetes and appears to affect glucose metabolism in an undefined manner. Finally, the 3' untranslated region of PEA-15 has been cloned as a proto-oncogene, MAT-1, isolated from breast cancer cells. Hence, understanding the mechanism, of PEA-15 regulation of ERK signaling may have direct clinical relevance.
The specific aims of this project are to: (1) Determine the residues of PEA-15 that are necessary for ERK binding by mutational analysis; (2) Determine the molecular mechanism by which PEA-15 affects ERK signaling; (3) Analyze the expression of PEA-15 mRNA and protein; and (4) Examine the function of PEA-15 expression on cell behavior in both cultured cells and cells derived from PEA-15 null mice. This work will illuminate the functional significance of PEA-15 and the molecular mechanism by which it acts. At the conclusion of these studies we will better understand how alterations in cell adhesion, migration, survival, and proliferation can be regulated by a novel player in cell signaling events. Moreover, this work will elucidate the potential role of PEA-15 in the pathogenesis of cancer and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA093849-01
Application #
6421427
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Ault, Grace S
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$258,519
Indirect Cost
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Greig, Fiona H; Kennedy, Simon; Gibson, George et al. (2017) PEA-15 (Phosphoprotein Enriched in Astrocytes 15) Is a Protective Mediator in the Vasculature and Is Regulated During Neointimal Hyperplasia. J Am Heart Assoc 6:
Sulzmaier, Florian J; Young-Robbins, Shirley; Jiang, Pengfei et al. (2016) RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics. Oncotarget 7:79869-79884
Gawecka, Joanna E; Young-Robbins, Shirley S; Sulzmaier, Florian J et al. (2012) RSK2 protein suppresses integrin activation and fibronectin matrix assembly and promotes cell migration. J Biol Chem 287:43424-37
Gawecka, Joanna E; Geerts, Dirk; Koster, Jan et al. (2012) PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma. Int J Cancer 131:1556-68
Sulzmaier, F J; Valmiki, M K G; Nelson, D A et al. (2012) PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D. Oncogene 31:3547-60
Hunter, Irene; Mascall, Keith S; Ramos, Joe W et al. (2011) A phospholipase C?1-activated pathway regulates transcription in human vascular smooth muscle cells. Cardiovasc Res 90:557-64
Gawecka, Joanna E; Griffiths, Genevieve S; Ek-Rylander, Barbro et al. (2010) R-Ras regulates migration through an interaction with filamin A in melanoma cells. PLoS One 5:e11269
Pastorino, Sandra; Renganathan, Hemamalini; Caliva, Maisel J et al. (2010) The death effector domain protein PEA-15 negatively regulates T-cell receptor signaling. FASEB J 24:2818-28
Valmiki, M Gudur; Ramos, J W (2009) Death effector domain-containing proteins. Cell Mol Life Sci 66:814-30
Ramos, Joe W; Townsend, David A; Piarulli, Dawn et al. (2009) Deletion of PEA-15 in mice is associated with specific impairments of spatial learning abilities. BMC Neurosci 10:134

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