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Principal Investigator: Miho Iijima
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $516,338
Funding agency: National Institute of General Medical Sciences
Summary (30 lines)
Our research program aims to understand how cells control intracellular signaling to respond and adapt to their
environments. We will focus on three processes: Project 1 will examine the chemotactic migration of cells in
extracellular chemical gradients, Project 2 will look at DNA repair after oxidative, genotoxic, and mechanical
stress, and Project 3 will investigate the reprogramming of cell proliferation signaling in response to receptor
tyrosine kinase inhibition.
Project 1: GTPases are crucial for signal transduction in many cellular activities. Recently, we discovered an
unforeseen, evolutionarily conserved mechanism by which GDP-bound Rho GTPase activates mTORC2, a
critical serine/threonine kinase, in Dictyostelium and human cells. We will investigate the fundamental
mechanism underlying this novel regulation of small GTPases using the robust chemotactic signaling in
Dictyostelium cells as a discovery tool supported by an array of cutting-edge technologies. Successful
outcomes will broadly impact tissue development, wound healing, neuronal wiring, and immune responses, as
chemotaxis is crucial for these essential processes.
Project 2: PTEN protects the genome from stress in the nucleus. PTEN accumulates in the nucleus upon
stress via ubiquitin signaling. Identifying the ubiquitin ligase that controls PTEN after stress represents a critical
knowledge gap in our understanding of PTEN's stress signaling. Using a genome-wide CRISPR screen, we
will comprehensively test the function of E3 ligases under various forms of stress, such as oxidative, genotoxic,
and mechanical stress. We will subsequently investigate how stress regulates the ubiquitin ligases.
Project 3: Cells can adapt to unfavorable surroundings and weakened physiology by rearranging signal
transduction pathways. We will analyze how cells alter signaling networks when the activity of vital signaling
components is inhibited using innovative approaches, including AI-based multiplexed biosensor barcoding. We
focus on the EGF receptor, which is essential for physiology and development. Outcomes will reveal the basic
mechanisms by which cells can rewire signal transduction pathways and bypass the inhibition of essential
signaling elements.
Terms: <APF-1><ATP-Dependent Proteolysis Factor 1><Bar Codes><Binding><Biosensor><Body Tissues><Bypass><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Reprogramming><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Cellular Proliferation><Chemicals><Chemotaxis><DNA Damage Repair><DNA Repair><Development><Dictyostelium><Disease><Disorder><E3 Ligase><E3 Ubiquitin Ligase><EGF Receptor><EGFR><ERBB Protein><Elements><Environment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><GTP Phosphohydrolases><GTPases><Generalized Growth><Genome><Genotoxic Stress><Growth><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><HER1><HMG-20><High Mobility Protein 20><Human><Immune response><Immunological response><Intracellular Communication and Signaling><Knowledge><L-Serine><MMAC1><MMAC1 protein><Mechanical Stress><Modern Man><Molecular Interaction><Monomeric G-Proteins><Monomeric GTP-Binding Proteins><Motility><Mutated in Multiple Advanced Cancers 1><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nucleus><Organism-Level Process><Organismal Process><Outcome><Oxidative Stress><PHTS gene><PHTS protein><PTEN><PTEN gene><PTEN protein><PTEN1><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Physiologic Processes><Physiological Processes><Physiology><Process><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Regulation><Research><Serine><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Small G-Proteins><Small GTPases><Stress><TGF-alpha Receptor><Technology><Testing><Therapeutic Intervention><Threonine Kinase><Tissue Growth><Tissues><Transforming Growth Factor alpha Receptor><Tyrosine Kinase Receptor Inhibition><Ubiquitin><Ubiquitin Ligase Component Gene><Ubiquitin Ligase Gene><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Unscheduled DNA Synthesis><Urogastrone Receptor><Wound Repair><barcode><biological adaptation to stress><biological sensor><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cell motility><cellular reprogramming><clustered regularly interspaced short palindromic repeats screen><developmental><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><extracellular><genome scale><genome-wide><genomewide><guanosinetriphosphatase><host response><immune system response><immunoresponse><innovate><innovation><innovative><intervention therapy><mutated in multiple advanced cancers 1 protein><neuronal><novel><ontogeny><phosphatase and tensin homologue on chromosome ten><programs><proto-oncogene protein c-erbB-1><reaction; crisis><response><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><stress response><stress; reaction><support tools><therapeutic agent development><therapeutic development><ubiquitin ligase><ubiquitin-protein ligase><wound healing><wound recovery><wound resolution>