The protein tyrosine phosphatase superfamily, all of which contain a highly conserved active site motif, Cys- X5-Arg (CX5R) are key mediators of a wide variety of cellular processes, including growth, metabolism, differentiation, motility, and programmed cell death. Our laboratory has demonstrated that some phosphatases harboring CX5R motifs utilize phosphoinositides instead of phosphoproteins as their physiological substrates. This includes the myotubularin (MTM) subfamily that removes the 3-phosphate from phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2. Mutations in MTM family members have been shown to cause the human neuromuscular disorders myotubular myopathy and Charcot-Marie-Tooth disease (CMT). This proposal will continue to study the regulation of the MTM family of PTPs as well as another novel phosphatase known as PTPMT1. In the next five years, we plan to develop a better understanding of how levels of PI(3)P transmit signals in the cell. First, we will explore the roles of MTMR2 and MTMR13 with respect to a new protein known as Frabin.which senses changes in PI(3)P levels resulting in the modulation of the activity of CDC42 and other Rho-like GTPases. Specifically, we will examine Frabin's role in mediating PI(3)P signal transduction events in Schwann cells, cells that produce myelin for insulating axons. We will then determine if this signal transduction pathway is widely used in other cell types. Second, we have demonstrated that PTPMT1 regulates insulin secretion by decreasing ATP production in INS-1 cells. In order to address PTPMTI's mechanism of action, we genetically engineered mice in which the PTPMT1 gene has been ablated. We are characterizing these mice phenotypically and will combine a series of systemic and biochemical approaches to study the role of PTPMT1 in cellular and whole animal contexts.

Public Health Relevance

Work on MTMR2, MTMR13, and Frabin will further our understanding of the neurodegenerative disorder, CMT. CMT is the most frequent class of inherited disorders of the peripheral nervous system. Work on PTPMT1 will give us a better understanding of how the cell regulates insulin secretion which is an important parameter in Type II diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK018024-40
Application #
8514576
Study Section
Special Emphasis Panel (NSS)
Program Officer
Silva, Corinne M
Project Start
1991-10-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
40
Fiscal Year
2013
Total Cost
$384,605
Indirect Cost
$135,670
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wen, Jianzhong; Xiao, Junyu; Rahdar, Meghdad et al. (2014) Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis. Proc Natl Acad Sci U S A 111:15723-8
Tagliabracci, Vincent S; Engel, James L; Wiley, Sandra E et al. (2014) Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A 111:5520-5
Bahmanyar, Shirin; Biggs, Ronald; Schuh, Amber L et al. (2014) Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown. Genes Dev 28:121-6
Worby, Carolyn A; Dixon, Jack E (2014) PTEN. Annu Rev Biochem 83:641-69
Bordoli, Mattia R; Yum, Jina; Breitkopf, Susanne B et al. (2014) A secreted tyrosine kinase acts in the extracellular environment. Cell 158:1033-44
Tagliabracci, Vincent S; Pinna, Lorenzo A; Dixon, Jack E (2013) Secreted protein kinases. Trends Biochem Sci 38:121-30
Xiao, Junyu; Tagliabracci, Vincent S; Wen, Jianzhong et al. (2013) Crystal structure of the Golgi casein kinase. Proc Natl Acad Sci U S A 110:10574-9
Wiley, Sandra E; Andreyev, Alexander Y; Divakaruni, Ajit S et al. (2013) Wolfram Syndrome protein, Miner1, regulates sulphydryl redox status, the unfolded protein response, and Ca2+ homeostasis. EMBO Mol Med 5:904-18
Tagliabracci, Vincent S; Xiao, Junyu; Dixon, Jack E (2013) Phosphorylation of substrates destined for secretion by the Fam20 kinases. Biochem Soc Trans 41:1061-5
Teh, Phildrich G; Chen, Mark J; Engel, James L et al. (2013) Identification of a mammalian-type phosphatidylglycerophosphate phosphatase in the Eubacterium Rhodopirellula baltica. J Biol Chem 288:5176-85

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