Differential phosphorylation of Akt1 and Akt2 by protein kinase CK2 may account for isoform specific functions.
Akt (also known as PKB) is a survival kinase frequently up-regulated in cancer; three isoforms of Akt exist, and among them Akt1 and Akt2 are the most widely and highly expressed. They share the same structure and activation mechanism and have many overlapping functions; nevertheless isoform-specific roles and substrates have been reported, which are expected to rely on sequence diversities. In particular, a special role in differentiating Akt1 and Akt2 isoforms has been assigned to the linker region, a short segment between the PH and the catalytic domains. We have previously found that a residue in the linker region (Ser129) is directly phosphorylated by protein kinase CK2 in Akt1; the phosphorylation of the homologous residue in Akt2 (Ser131) has never been analyzed. Here we show that Akt2, endogenously or ectopically expressed in different cell lines, is not phosphorylated on Ser131 by CK2, while in vitro recombinant Akt2 is a CK2 substrate. These data support the hypothesis that in vivo a steric hindrance occurs which prevents the access to the CK2 site. Additionally, we have found that Ser129 phosphorylation is involved in the recognition of the Akt1-specific substrate palladin; this observation provides an explanation of why Akt2, lacking Ser131 phosphorylation in the linker region, has a low efficiency in targeting palladin. CK2-dependent phosphorylation is therefore a crucial event which, discriminating between Akt1 and Akt2, can account for different substrate specificities, and, more in general, for fine tuning of Akt activity in the control of isoform-dependent processes.
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/b, 35131 Padova, Italy; CNR Institute of Neurosciences, Via U. Bassi 58/b, 35131 Padova, Italy.
Cristina
C
Girardi
Lund University, BMC D13, Immunotechnology, Lund 221, Sweden.
Peter
P
James
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/b, 35131 Padova, Italy; CNR Institute of Neurosciences, Via U. Bassi 58/b, 35131 Padova, Italy.
Sofia
S
Zanin
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/b, 35131 Padova, Italy; CNR Institute of Neurosciences, Via U. Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via G. Orus 2, 35129 Padova, Italy.
Lorenzo A
LA
Pinna
Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/b, 35131 Padova, Italy; CNR Institute of Neurosciences, Via U. Bassi 58/b, 35131 Padova, Italy; Venetian Institute of Molecular Medicine, Via G. Orus 2, 35129 Padova, Italy. Electronic address: maria.ruzzene@unipd.it.
Maria
M
Ruzzene
D000595:Amino Acid Sequence; D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011489:Protein Denaturation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D003598:Cytoskeletal Proteins; D004220:Disulfides; D007527:Isoenzymes; C412722:PALLD protein, human; D010748:Phosphopeptides; D010750:Phosphoproteins; D011994:Recombinant Proteins; D010768:Phosphoserine; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt
Akt; CK2; CKII; Casein kinase 2; Isoform specificity; PKB