This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. T cell acute lymphoblastic leukemia/lymphoma (TALL/L) involves abnormal proliferation of lymphocytes, or white blood cells. TALL/L patients often show elevated levels of the active form of the oncoprotein, RasGTP, in blood and bone marrow cells. In contrast to other cancers, few of these TALL/L patients have the typical mutations in Ras protein that would explain this accumulation. This finding suggests that many TALL/L patients have abnormal expression or activity of signaling proteins upstream of RasGTP. Lymphocytes express two Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP1, which work together to activate Ras when cell surface receptors are stimulated. Previous work demostrated that RasGRP1 is the dominant RasGEF in lymphocytes after antigen receptor stimulation. Mice overexpressing wild type RasGRP1 develop thymomas and skin carcinomas. Thus non-cancerous cells must have a mechanism to limit RasGRP1 function. Surprisingly, the negative regulatory factors that turn off this strong, RasGRP1-driven growth signal and prevent uncontrolled proliferation are unknown. Control of signals received via receptor binding can occur through posttranslational modification of signaling components. Decreases in RasGRP1 protein level after T cell receptor (TCR) stimulation precedes RasGRP1 transcript degradation. This study will identify the posttranslational modification events controlling RasGRP1 protein levels and activity within lymphocytes. The proposed experiments will use Mass Spectrometry to examine posttranslational modification events that occur on RasGRP1 protein following TCR stimulation. Modified sites identifed will give us insight into the control of RasGRP1 activity in normal lymphocytes and provide mechanistic clues for TALL/L patient samples with mutated forms of RasGRP1.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001614-29
Application #
8363811
Study Section
Special Emphasis Panel (ZRG1-BCMB-M (40))
Project Start
2011-06-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
29
Fiscal Year
2011
Total Cost
$630
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
MacRae, Andrew J; Mayerle, Megan; Hrabeta-Robinson, Eva et al. (2018) Prp8 positioning of U5 snRNA is linked to 5' splice site recognition. RNA 24:769-777
Katsuno, Yoko; Qin, Jian; Oses-Prieto, Juan et al. (2018) Arginine methylation of SMAD7 by PRMT1 in TGF-?-induced epithelial-mesenchymal transition and epithelial stem-cell generation. J Biol Chem 293:13059-13072
Sahoo, Pabitra K; Smith, Deanna S; Perrone-Bizzozero, Nora et al. (2018) Axonal mRNA transport and translation at a glance. J Cell Sci 131:
Tran, Vy M; Wade, Anna; McKinney, Andrew et al. (2017) Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion. Mol Cancer Res 15:1623-1633
Liu, Tzu-Yu; Huang, Hector H; Wheeler, Diamond et al. (2017) Time-Resolved Proteomics Extends Ribosome Profiling-Based Measurements of Protein Synthesis Dynamics. Cell Syst 4:636-644.e9
Kintzer, Alexander F; Stroud, Robert M (2016) Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana. Nature 531:258-62
Bikle, Daniel D (2016) Extraskeletal actions of vitamin D. Ann N Y Acad Sci 1376:29-52
Twiss, Jeffery L; Fainzilber, Mike (2016) Neuroproteomics: How Many Angels can be Identified in an Extract from the Head of a Pin? Mol Cell Proteomics 15:341-3
Cil, Onur; Phuan, Puay-Wah; Lee, Sujin et al. (2016) CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2:317-327
Posch, Christian; Sanlorenzo, Martina; Vujic, Igor et al. (2016) Phosphoproteomic Analyses of NRAS(G12) and NRAS(Q61) Mutant Melanocytes Reveal Increased CK2? Kinase Levels in NRAS(Q61) Mutant Cells. J Invest Dermatol 136:2041-2048

Showing the most recent 10 out of 630 publications