Phosphorylation of proteins on tyrosyl residues is a key mechanism for the control of cell growth, differentiation and development. Phosphate is selectively removed from tyrosyl residues by a family of enzymes known as protein tyrosine phosphatases (PTPases), which play important roles in preventing malignant transformation, limiting signal transduction and in the maintenance of normal cell physiology. This proposal focuses on one particular PTPase, the 68-kDa PTP-MEG2, which contains a novel type of phospholipid-binding domain, a CRASH domain. We have found that this domain binds phosphatidylinositol-3,4,5-trisphosphate (Ptdlns(3,4,5)P3) with high affinity and that PTP-MEG2 is located on secretory vesicles in mast cells, T cells, and other cell types. We hypothesize that the physiological function of PTP-MEG2 is to regulate the formation or homeostasis of dense-core secretory vesicles of the regulated secretory pathway in hematopoietic and other cells. We will focus on this topic by addressing the following 3 specific aims: 1) Regulation of PTP-MEG2 by inositol phospholipids. 2) Identification of substrates for PTP-MEG2. 3) Physiological function of PTP-MEG2. Our overall goal is to understand the physiological function of PTPases in tyrosine phosphorylation-mediated cellular processes. PTP-MEG2 is a unique member of this class of enzymes and appears to integrate phosphoinositide signaling into tyrosine dephosphorylation and the regulation of intracellular vesicle traffic. This represents a novel and unexpected crosstalk between these three important aspects of cell biology. Thus, the significance of our work is high and it may bring many new insights that could be exploited for the treatment of human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI055741-01
Application #
6662338
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mallia, Conrad M
Project Start
2003-09-30
Project End
2008-01-31
Budget Start
2003-09-30
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$111,416
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mustelin, Tomas (2007) A brief introduction to the protein phosphatase families. Methods Mol Biol 365:9-22
Makagiansar, Irwan T; Williams, Scott; Mustelin, Tomas et al. (2007) Differential phosphorylation of NG2 proteoglycan by ERK and PKCalpha helps balance cell proliferation and migration. J Cell Biol 178:155-65
Saito, Kan; Tautz, Lutz; Mustelin, Tomas (2007) The lipid-binding SEC14 domain. Biochim Biophys Acta 1771:719-26
Saito, Kan; Williams, Scott; Bulankina, Anna et al. (2007) Association of protein-tyrosine phosphatase MEG2 via its Sec14p homology domain with vesicle-trafficking proteins. J Biol Chem 282:15170-8
Mustelin, Tomas (2006) Are other protein tyrosine phosphatases than PTPN22 associated with autoimmunity? Semin Immunol 18:254-60
Nika, Konstantina; Charvet, Celine; Williams, Scott et al. (2006) Lipid raft targeting of hematopoietic protein tyrosine phosphatase by protein kinase C theta-mediated phosphorylation. Mol Cell Biol 26:1806-16
Mustelin, Tomas (2006) Protein tyrosine phosphatases in human disease. Adv Exp Med Biol 584:53-72
Tautz, Lutz; Pellecchia, Maurizio; Mustelin, Tomas (2006) Targeting the PTPome in human disease. Expert Opin Ther Targets 10:157-77
Merkulova, Maria; Huynh, Huong; Radchenko, Vitaly et al. (2005) Secretion of the mammalian Sec14p-like phosphoinositide-binding p45 protein. FEBS J 272:5595-605
Mena-Duran, Armando V; Togo, Summanuna H; Bazhenova, Lyudmila et al. (2005) SHP1 expression in bone marrow biopsies of myelodysplastic syndrome patients: a new prognostic factor. Br J Haematol 129:791-4

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