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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-03-0851.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2804-2809
PHAGOCYTES
Felic (CIP4b), a novel binding partner with the Src kinase
Lyn and Cdc42, localizes to the phagocytic cup
Patrice Dombrosky-Ferlan,
Anatoly Grishin,
Roberto J. Botelho,
Matthew Sampson,
Lin Wang,
William A. Rudert,
Sergio Grinstein, and
Seth J. Corey
From the Department of Pediatrics, Department of
Pharmacology, University of Pittsburgh, PA; the Department of
Biochemistry, University of Toronto, ON, Canada; and the
Programme in Cell Biology, Hospital for Sick Children, Toronto, ON,
Canada.
Through its Src homology 3 (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 2-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). Felic was expressed in
both hematopoietic and nonhematopoietic tissues. Because it represents
an alternative splice product related to the Cdc42-interacting protein
4, 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 in its activated form only.
Unlike CIP4, Felic does not possess a C-terminal SH3 domain.
Coprecipitation studies show that Felic bound to Lyn or activated forms
of Cdc42. Overexpression 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 constitute 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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