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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3650-3657
HEMATOPOIESIS
A cytoplasmic serine protein kinase binds and may regulate
the Fanconi anemia protein FANCA
Hiroshi Yagasaki,
Daiki Adachi,
Tsukasa Oda,
Irene Garcia-Higuera,
Nii Tetteh,
Alan D. D'Andrea,
Makoto Futaki,
Shigetaka Asano, and
Takayuki Yamashita
From the Division of Genetic Diagnosis, Institute of
Medical Science; and the Department of Molecular Therapy, Advanced
Clinical Research Center, Institute of Medical Science, University of
Tokyo, Japan; and the Department of Pediatric Oncology, Dana-Farber
Cancer Institute, Harvard Medical School, Boston, MA.
Fanconi anemia (FA) is an autosomal recessive disease with
congenital anomalies, bone marrow failure, and susceptibility to leukemia. Patient cells show chromosome 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 protein 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 phosphorylation was
defective in those derived from patients with FA of multiple
complementation groups. The present study examined phosphorylation of
FANCA ectopically expressed in FANCA cells. Several
patient-derived mutations abrogated in vivo phosphorylation 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 appears to be another component of the FA protein complex and
may regulate function of FANCA. FANCA-PK was characterized as a
cytoplasmic serine kinase sensitive to wortmannin. Identification of
the protein kinase is expected to elucidate regulatory mechanisms that
control the FA pathway.
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