Protein kinase B

from Wikipedia, the free encyclopedia
Protein kinase Bα
Properties of human protein
Mass / length primary structure 480 amino acids
Identifier
Gene names AKT1  ; RAC; PKB
External IDs
Enzyme classification
EC, category 2.7.11.1 ,  protein kinase
Response type Phosphorylation
Substrate ATP + TBC1D4, IKBKA, BAD, Caspase-9, FOXO3A, FKHRL1, NOS3, EDG1, Tsc2, p27, Huntingtin, EZH2
Products ADP + protein phosphate
Occurrence
Homology family ST protein kinase
Parent taxon Eukaryotes

Protein kinase Bβ
Properties of human protein
Mass / length primary structure 481 amino acids
Identifier
Gene name ACT2
External IDs
Enzyme classification
EC, category 2.7.11.1 ,  protein kinase
Response type Phosphorylation
Substrate ATP + PGC1-α
Products ADP + protein phosphate

Protein kinase Bγ
Properties of human protein
Mass / length primary structure 479 amino acids
Isoforms PKBγ PKBγ1
Identifier
Gene names AKT3  ; PKBG; RAC-γ
External IDs
Enzyme classification
EC, category 2.7.11.1 ,  protein kinase
Response type Phosphorylation
Substrate ATP + protein
Products ADP + protein phosphate

The protein kinases B (PKBα / β / γ) ( genes : AKT1 , AKT2 , AKT3 ) are three enzymes that transfer a phosphate group to other proteins ( protein kinases ). The proteins modified in this way are part of important signaling pathways in the body, and thus the PKB themselves are part of signal transduction . The serine / threonine kinases, to which the PKB belong, evolved with the eukaryotes . PKBα is produced in all tissue types in humans, as is PKBγ, but to a lesser extent. PKBβ is mainly expressed in insulin-sensitive tissues. Since PKBs are often overactive in tumor cells, AKT1 / 2/3 are oncogenes .

Identification of the AKT genes

The prototype AKT gene AKT1 was discovered in 1991 by three groups. The groups of Brian Hemmings and J. R. Woodgett used homologous cloning to search for cellular kinases that are similar to the protein kinases PKA and PKC and named these kinases PKBα and RAC-PK (protein kinase - related to PKA & PKC). Tsichlis' group, however, characterized a viral oncogene - v-AKT - as a transforming agent in the poorly characterized retrovirus AKT8 and thus found the viral counterpart to the eukaryotic serine / threonine kinase . A little later, the highly homologous isoforms AKT2 and AKT3 were cloned.

Isoforms and structure

All three AKT genes code for the protein kinase isoforms AKT1 / PKB α , AKT2 / PKB β and AKT3 / PKB γ, which are highly homologous in their peptide sequence , with a central N-terminal PH domain (PH = pleckstrin homology ) Kinase domain and a C-terminal hydrophobic domain with regulatory function. There are two splicing variants of AKT3 / PKB γ with different C-terminal ends.

Regulation of its kinase activity

For adequate cell homeostasis , the activity of the kinase has to be controlled via various mechanisms:

  • Secondary messenger substances ( phospholipid derivatives)
  • Post-translational modifications
    • activating phosphorylations T308, S473 by other kinases
    • Auto-phosphorylation
    • Trans-phosphorylation
  • Protein-protein interactions
    • Oligomerization with the oncogene TCL1

PKB signaling pathway

Protein kinase B plays a central role in the regulation of various cellular processes such as growth, cell proliferation , cell cycle and metabolism .

In the signal path above the PKB, it is the phosphoinositide-3-kinase (PI3K) activated by extracellular signals that initiates the so-called PI3K / AKT signal path by generating the secondary messenger substances PIP 3 from phosphatidylinositol-4,5-bisphosphate (PIP 2 ) .

Protein kinase B can bind to PIP 3 with its PH domain and thereby be recruited to the cell membrane . There it is phosphorylated by the phosphoinositide-dependent kinase-1 (PDK1) and another kinase at its amino acids serine (473) and threonine (308) and thereby activated. Activated PKB can then phosphorylate various substrates and thereby activate or inhibit them. One enzyme that counteracts this mechanism is the phosphatase PTEN , which inactivates PIP 3 by splitting off a phosphate group. PTEN is a typical tumor suppressor and is inactivated by mutations in many tumor clones. Such tumor cells with a loss-of-function in PTEN and a resulting overactive PKB are proliferative tumors with frequent resistance to chemotherapeutic agents .

There are also a number of other proteins that interact directly with PKB and influence their activity. A well-known one is TCL1 , which can oligomerize in the cytosol with AKT via its PH domain and leads to activation of the kinase activity and changes in the subcellular localization of AKT. It was shown in biochemical assays that a TCL1 dimer interacts with 2 AKT molecules.

Substrates and Physiological Consequences

There are a number of alleged and described substrates of protein kinase B that have very different physiological consequences. They all have the consensus sequence RXRXXS / TB . Known target proteins of Akt are Bcl-2 proteins and proteases that play a role in apoptosis , forkhead transcription factors , and inhibitors of CDKs . The following table is adapted from Manning & Cantley (2007).

protein Phosphorylation site effect
FOXO1 T24, S256, S319 Inhibited
FOXO3 T32, S253, S315 Inhibited
FOXO4 T32, S197, S262 Inhibited
TSC2 S939, T1462 Inhibited
GSK3 α , β S21 / S9 Inhibited
RAF1 S259 Inhibited
PRAS40 T246 Inhibited
AS160 S588, T642 Inhibited
Bcl-2 antagonist of cell death (BAD) S99 Inhibited
WNK1 T60 ?
MDM2 S166 Activated
Chk1 S280 Inhibited
eNOS S1177 Activated
ASK1 S83 Inhibited
IKK α T23 Activated
p21 CIP1 T157 Inhibited
p27 KIP1 T157 Inhibited
Caspase -9 S196 Inhibited

PKB / nude and cancer

The fact that the AKT8 retrovirus can induce T-cell lymphoma in mice underscored the importance of protein kinase B in transformation and carcinogenesis and led many groups to direct their research in this direction. Due to its transformative property, PKB / AKT can be called an oncogene .

ACT (E17K)

A mutation was found in the PH domain of AKT1 that can cause cancer. This is a point mutation (G> A) at nucleotide  49, which leads to the exchange of amino acid 17 of the PH domain (glutamic acid is replaced by lysine). This AKT mutant is called AKT (E17K) .

The mutation changes the conformation of the PH domain and AKT can bind to the membrane (and be activated there), even if there is no PIP 3 there. A regulation of the ACT activation via the PIP phosphorylation or the PI3 kinase activity is no longer possible.

The said mutant was found in 8% of breast cancers , 6% of colorectal cancers and 2% of ovarian cancers .

The activity of the individual kinase is as great as that of the wild type ; however, due to the frequent membrane association, more kinases are permanently active than in wild-type cells. As a result, anti- apoptotic and proliferation- promoting signal pathways are increasingly activated, which can ultimately lead to the degeneration of the cells. In mice, for example, the mutant causes leukemia with a probability of 60% (wild type: 0%).

literature

  • Bellacosa et al .: A Portrait of AKT kinases . In: Cancer Biology and Therapy , 3, 2004, 3, pp. 268-275.
  • Tokerm Yoeli-Lerner: Akt Signaling and Cancer: Surviving but not Moving on . In: Cancer Research , 66: (8), April 15, 2006.

Web links

Individual evidence

  1. ^ G Künstle, J Laine, G Pierron, S Kagami Si, H Nakajima, F Hoh, C Roumestand, MH Stern, M. Noguchi: Identification of Akt association and oligomerization domains of the Akt kinase coactivator TCL1. In: Mol Cell Biol. , 2002 Mar, 22 (5), pp. 1513-1525. PMID 11839817
  2. ^ DR Alessi, FB Caudwell, M Andjelkovic, BA Hemmings, P. Cohen: Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. In: FEBS Lett . , 1996 Dec 16,399 (3), pp. 333-338, PMID 8985174
  3. ^ BD Manning, LC. Cantley: AKT / PKB signaling: navigating downstream. In: Cell , 2007 Jun 29, 129 (7), pp. 1261-1274. Review PMID 17604717
  4. ↑ A transforming mutation in the pleckstrin homology domain of AKT1 in cancer . In: Nature , Vol. 448, July 26, 2007, pp. 439-444