Through its SH3 and SH2 domains, the Src kinase Lyn interacts with a small number of phosphoproteins, such as Shc, Cbl, and Vav, which regulate cell cycle and the cytoskeleton. Using Lyn's Unique, SH3, and SH2 domains as bait in a yeast two-hybrid screen, we isolated a gene with features of a scaffolding protein, CIP4. We have identified its four isoforms. CIP4 contains a conserved N-terminal domain, a putative coiled-coil domain, and a C-terminal SH3 domain. What makes CIP4 particularly fascinating to study is its ability to bind two sets of distinct cytoskeletal proteins and their activators. Cytoskeletal reorganization, essential for normal as well as neoplastic cellular function, requires a complex set of protein interactions. CIP4 binds Src kinases and activated states of the RhoGTPase Cdc42. Also, CIP4 binds microtubules through its N-terminal Fes/CIP4 Homologous (FCH) domain and proline-rich proteins such as WASp through its C-terminal SH3 domain. CIP4 belongs to a newly described family of proteins found in lower eukaryotes such yeast. In mammals, we hypothesize that CIP4 plays an important role in Fc Receptor or adhesion-induced integrin signal transduction in leukocytes by providing a scaffold and linking the cytoskeletal system to Src kinases and Cdc42. The resulting cytoskeletal rearrangement is required for cell spreading, migration and functional activation. We hypothesize that CIP4 is a critical scaffolding protein that brings together Lyn and recruits WASp to the plasma membrane in the quiescent cell, and that upon receptor engagement, Lyn becomes activated, phosphorylates WASp, and CIP4 facilitates the recruitment of activated Cdc42 which drives WASp unfolding. Arp2/3 becomes activated, and actin nucleation commences. This localized cytoskeletal assembly contributes to phagosome/podosome formation. We further hypothesize that the SH3 domain and the h-insert mediate different signaling functions among the CIP4 isoforms. To address these hypotheses, we propose the following specific aims:
Specific Aim 1 : Determine the contribution of the CIP4 domains on cytoskeletal function, and Specific Aim 2: Determine the temporal and spatial relationships among CIP4, Cdc42, Lyn and WASp in macrophages during cytoskeletal assembly. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080052-04
Application #
7371961
Study Section
Special Emphasis Panel (ZRG1-ELB (01))
Program Officer
Mondoro, Traci
Project Start
2005-01-01
Project End
2008-05-31
Budget Start
2008-01-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$209,190
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Mehta, Hrishikesh M; Malandra, Michael; Corey, Seth J (2015) G-CSF and GM-CSF in Neutropenia. J Immunol 195:1341-9
Glaubach, Taly; Robinson, Lisa J; Corey, Seth J (2014) Pediatric myelodysplastic syndromes: they do exist! J Pediatr Hematol Oncol 36:1-7
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Mehta, Hrishikesh M; Glaubach, Taly; Corey, Seth Joel (2014) Systems approach to phagocyte production and activation: neutrophils and monocytes. Adv Exp Med Biol 844:99-113
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Chen, Yolande; Aardema, Jorie; Corey, Seth J (2013) Biochemical and functional significance of F-BAR domain proteins interaction with WASP/N-WASP. Semin Cell Dev Biol 24:280-6
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Feng, Yanming; Hartig, Sean M; Bechill, John E et al. (2010) The Cdc42-interacting protein-4 (CIP4) gene knock-out mouse reveals delayed and decreased endocytosis. J Biol Chem 285:4348-54

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