Cell Type and Stimulus-Specific Signaling Role of CDC42 in Blood

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

The long-term objective of this project is to understand the role and unique signaling mechanism of[unreadable] the Rho family small GTPase Cdc42 in mammalian cells of various lineages. Current biochemical model[unreadable] depicts that upon ligand binding to cell surface receptors or in response to cellular stress, Cdc42 is activated[unreadable] to recognize specific downstream effectors to regulate multiple cell functions including actin reorganization,[unreadable] adhesion, migration, vesicle trafficking and cell cycle progression. To date, however, most studies of Cdc42[unreadable] function in mammalian cells have been carried out by overexpressing dominant negative or constitutively[unreadable] active Cdc42 mutants in clonal cell lines; the physiologic role and signaling mechanism of Cdc42 in most[unreadable] primary cell lineages have yet to be examined genetically. We have generated the Cdc42 conditional[unreadable] knockout mice by a loxP/Cre recombination strategy to allow targeted deletion of Cdc42 in adult or[unreadable] embryonic tissues including various hematopoietic organs, and have produced a Cdc42 gain of activity[unreadable] mouse model by gene targeting of a Cdc42 negative regulator, Cdc42GAP, that causes a global[unreadable] upregulation of Cdc42 activity in most cell types. Based on our preliminary studies of cells derived from[unreadable] these Cdc42 loss or gain of activity mice, we hypothesize that Cdc42 regulates cell growth, migration and[unreadable] other cell-type specific functions in a cell- and stimulus-specific manner. To define the Cdc42 signaling[unreadable] mechanisms in mammalian primary cells that may not be revealed by conventional means, in this proposal[unreadable] we will utilize the Cdc42 loss and gain of activity mouse models (1) to study the role and signaling[unreadable] mechanism of Cdc42 in the hematopoietic stem/progenitor cell (HSC) lineage; (2) to determine the[unreadable] involvement of Cdc42 in regulating the unique functions of the HSC- differentiated mast cells, and (3) to[unreadable] examine the structure-function relationship of Cdc42 in the HSC and mast cells by a reconstitution approach.[unreadable] Human disease relevance: The results may implicate Cdc42 in hematopoietic stem/progenitor and mast cell[unreadable] regulation and associate Cdc42 mulfunction with human hematopoietic stem/progenitor and mast cell[unreadable] disorders such as leukemia and inflammation.