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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-03-0851.
Submitted March 19, 2002
Accepted November 10, 2002
Felic (CIP4b), a novel binding partner with the Src kinase Lyn and Cdc42, localizes to the phagocytic cup
Patrice Ferlan-Dombrosky, Anatoly Grishin, Roberto Botelho, Matthew Sampson, Lin Wang, William A Rudert, Sergio Grinstein, and Seth J Corey*
Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Pediatrics, MD Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: sjcorey{at}mdanderson.org.
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 novel gene product with features of a scaffolding protein. We named it Felic, because it contains a domain homologous to the tyrosine kinase Fes and the cytoskeletal protein Ezrin and forms a Lyn interaction with the GTPase Cdc42. Felic was expressed in both hematopoietic and non-hematopoietic tissues. Because it represents an alternative splice product related to the Cdc42-interacting protein, CIP4, we also refer to Felic as CIP4b. Felic contains an SH3 recognition site RXPXXP and multiple tyrosine residues. In insulin or serum stimulated HEK293 cells, Felic became tyrosine phosphorylated. Like CIP4, Felic associated with Cdc42 only in its activated form. Unlike CIP4, Felic does not possess a C-terminal SH3 domain. Co-precipitation studies show that Felic bound to Lyn or activated forms of Cdc42. Over-expression of Felic or CIP4 inhibited NIH 3T3 cell invasiveness in a Matrigel assay. Because Lyn and Cdc42 are involved in phagocytosis, we examined the distribution of Felic in RAW macrophages during particle ingestion. Felic was recruited more efficiently than CIP4 to the phagocytic cups. Altogether, these data suggest that CIP4/Felic constitutes a novel family of cytoskeletal scaffolding proteins, integrating Src and Cdc42 pathways. The absence of an SH3 domain in Felic provides a structural basis for functional differences.
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