HEMATOPOIESIS A cytoplasmic serine protein kinase binds and may regulate the

Fanconi anemia (FA) is an autosomal recessive disease with congenital anoma-lies, bone marrow failure, and susceptibil-ity to leukemia. Patient cells show chro-mosome instability and hypersensitivity to DNA cross-linking agents. At least 8 complementation groups (A-G) have been identified and 6 FA genes (for subtypes A, C, D2, E, F, and G) have been cloned. Increasing evidence indicates that a pro-tein complex assembly of multiple FA proteins, including FANCA and FANCG, plays a crucial role in the FA pathway. Previously, it was reported that FANCA was phosphorylated in lymphoblasts from normal controls, whereas the phosphory-lation was defective in those derived from patients with FA of multiple complementa-tion groups. The present study examined phosphorylation of FANCA ectopically ex-pressed in FANCA2 cells. Several patient-derived mutations abrogated in vivo phos-phorylation of FANCA in this system, suggesting that FANCA phosphorylation is associated with its function. In vitro phosphorylation studies indicated that a physiologic protein kinase for FANCA (FANCA-PK) forms a complex with the substrate. Furthermore, at least a part of FANCA-PK as well as phosphorylated FANCA were included in the FANCA/ FANCG complex. Thus, FANCA-PK ap-pears to be another component of the FA protein complex and may regulate func-tion of FANCA. FANCA-PK was character-ized as a cytoplasmic serine kinase sensi-tive to wortmannin. Identification of the protein kinase is expected to elucidate regulatory mechanisms that control the FA pathway. (Blood. 2001;98:3650-3657) © 2001 by The American Society of Hematolog