Under this grant we have discovered a number of G protein binding proteins, established their properties and revealed new roles for heterotrimeric G proteins in cells. During the current funding period we characterized GIV, a non-receptor GEF that activates G?I proteins. GIV serves as a multimodular signal transducer that assembles protein complexes and links G? subunits to other signaling pathways (growth factor and PI3K/Akt signaling) and to several important cell functions, including cell migration, autophagy, transport of secretory proteins, and endocytosis of growth factor receptors. GIV also binds G?s, promotes EGF receptor downregulation, and shuts down proliferative signaling from endosomes. The overall goal of the work proposed is to take advantage of the tools and insights we have developed to shed light on some well-known but poorly understood functions of G proteins especially on intracellular membranes. We will focus on two specific aims:
Specific Aim #1 : To pinpoint the mechanisms by which GIV and its interactions with G?I and G?s regulate EGFR trafficking and growth factor signaling. Our working model based on preliminary data is that GIV sequentially binds G?i3 and G?s after EGF stimulation and that phosphomodification of GIV regulates the relative binding to the two G proteins and determines whether cells migrate or proliferate.
Specific Aim #2 : To determine the role of G?i3 and GIV in Golgi functions and to define the mechanisms involved. Our data indicate that depletion of GIV or a GIV mutant that fails to activate G?i3 slows transport of newly synthesized proteins through the Golgi. Our working hypothesis based on preliminary data is that GIV does so by activating G?i3, down-regulating Arf1 activity, and facilitating vesicle uncoating. These studies can be expected to provide novel insights into how GIV binds and regulates two different G proteins and influences growth factor signaling, Golgi functions, cell migration and cell proliferation. Based on its crucil functions in regulating cell behavior, it is essential to define GIV's functions and interactions. Our studies will not only provide insights into fundamental roles of G proteins in cell functions, but also it may establish new paradigms that will help to identify new therapeutic targets for development of pharmacologic and anti-tumor agents. We are uniquely positioned to tackle these problems by taking advantage of the new tools, expertise, and information we have in hand.

Public Health Relevance

Under this grant we have discovered and characterized a number of new molecules that are part of novel G protein signaling networks which regulate many cell processes important in cancer research-- including endocytosis, growth and proliferation, cell migration and metastasis. The studies planned in this application which focus on GIV, a novel GEF for G?proteins, can be expected to shed light on new G protein functions in normal cells as well as to provide key insights into the molecular basis of the dysregulation of cell proliferation, mitosis and migration that occur in cancer and other diseases. Due to its crucial functions in cell regulation GIV represents an attractive target for development of pharmacologic and anti-tumor agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100768-15
Application #
9623323
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Yassin, Rihab R
Project Start
2003-04-17
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
15
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Aznar, Nicolas; Ear, Jason; Dunkel, Ying et al. (2018) Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple. Sci Signal 11:
Midde, Krishna; Sun, Nina; Rohena, Cristina et al. (2018) Single-Cell Imaging of Metastatic Potential of Cancer Cells. iScience 10:53-65
Lizcano, Anel; Secundino, Ismael; Döhrmann, Simon et al. (2017) Erythrocyte sialoglycoproteins engage Siglec-9 on neutrophils to suppress activation. Blood 129:3100-3110
Siddiqui, Shoib S; Springer, Stevan A; Verhagen, Andrea et al. (2017) The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool. J Biol Chem 292:15312-15320
Ghosh, Pradipta; Rangamani, Padmini; Kufareva, Irina (2017) The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block. Cell Cycle 16:607-612
Aznar, Nicolas; Sun, Nina; Dunkel, Ying et al. (2017) A Daple-Akt feed-forward loop enhances noncanonical Wnt signals by compartmentalizing ?-catenin. Mol Biol Cell 28:3709-3723
Ghosh, Pradipta (2017) The stress polarity pathway: AMPK 'GIV'-es protection against metabolic insults. Aging (Albany NY) 9:303-314
Aznar, Nicolas; Patel, Arjun; Rohena, Cristina C et al. (2016) AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin. Elife 5:
Banerjee Mustafi, Soumyajit; Aznar, Nicolas; Dwivedi, Shailendra Kumar Dhar et al. (2016) Mitochondrial BMI1 maintains bioenergetic homeostasis in cells. FASEB J 30:4042-4055
Aznar, Nicolas; Kalogriopoulos, Nicholas; Midde, Krishna K et al. (2016) Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time. Bioessays 38:379-93

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