title: c-Abl tyrosine kinase regulates serum-induced nuclear export of diacylglycerol kinase α by phosphorylation at Tyr-218.
abstract: c-Abl is a tyrosine kinase involved in many cellular processes, including cell cycle control and proliferation. However, little is known about its substrates. Here, we show that c-Abl directly phosphorylates diacylglycerol kinase α (DGKα), an important regulator of many cellular events through its conversion of diacylglycerol to phosphatidic acid. We found that DGKα was transported from the cytoplasm to the nucleus in response to serum starvation, and serum restoration induced the nuclear export of the enzyme to the cytoplasm. This serum-induced export involves two tyrosine kinases, c-Src and c-Abl. The latter, c-Abl, is activated by c-Src, phosphorylates DGKα, and shuttles between the nucleus and the cytoplasm in a direction opposite to that of DGKα in response to serum restoration. Moreover, an in vitro phosphorylation assay using purified mutants of DGKα identified Tyr-218 as a site of phosphorylation by c-Abl. We confirmed these results for endogenous DGKα using an antibody specific for phospho-Tyr-218, and this phosphorylation was necessary for the serum-induced export of DGKα. These results demonstrate that the nucleo-cytoplasmic shuttling of DGKα is orchestrated by tyrosine phosphorylation by the Src-activated tyrosine kinase c-Abl and that this phosphorylation is important for regulating the function of cytoplasmic and/or nuclear DGKα.
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Matsubara
authors.forename: Momo
authors.initials: M
authors.lastname: Ikeda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kiso
authors.forename: Megumi
authors.initials: M
authors.lastname: Sakuma
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshino
authors.forename: Fumio
authors.initials: F
authors.lastname: Sakane
authors.forename: Isabel
authors.initials: I
authors.lastname: Merida
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Shirai
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D019852:Diacylglycerol Kinase / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D044967:Serum / Q000378:metabolism*; D013552:Swine; D014443:Tyrosine; D019061:src-Family Kinases
chemical_list: D014443:Tyrosine; D019852:Diacylglycerol Kinase; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases