Drosophila Lk6 kinase controls phosphorylation of eukaryotic translation initiation factor 4E and promotes normal growth and development

TY - JOUR

T1 - Drosophila Lk6 kinase controls phosphorylation of eukaryotic translation initiation factor 4E and promotes normal growth and development

AU - Arquier, Nathalie

AU - Bourouis, Marc

AU - Colombani, Julien

AU - Léopold, Pierre

PY - 2005/1/11

Y1 - 2005/1/11

N2 - Eukaryotic initiation factor 4E (eIF4E) controls a crucial step of translation initiation and is critical for cell growth . Biochemical studies have shown that it undergoes a regulated phosphorylation by the MAP-kinase signal-integrating kinases Mnk1 and Mnk2 . Although the role of eIF4E phosphorylation in mammalian cells has remained elusive , recent work in Drosophila has established that it is required for growth and development . Here, we demonstrate that a previously identified Drosophila kinase called Lk6 is the functional homolog of mammalian Mnk kinases. We generated lk6 loss-of-function alleles and found that eIF4E phosphorylation is dramatically reduced in lk6 mutants. Importantly, lk6 mutants exhibit reduced viability, slower development, and reduced adult size, demonstrating that Lk6 function is required for organismal growth. Moreover, we show that uniform lk6 expression rescues the lethality of eIF4E hypomorphic mutants in an eIF4E phosphorylation site-dependent manner and that the two proteins participate in a common complex in Drosophila S2 cells, confirming the functional link between Lk6 and eIF4E. This work demonstrates that Lk6 exerts a tight control on eIF4E phosphorylation and is necessary for normal growth and development.

AB - Eukaryotic initiation factor 4E (eIF4E) controls a crucial step of translation initiation and is critical for cell growth . Biochemical studies have shown that it undergoes a regulated phosphorylation by the MAP-kinase signal-integrating kinases Mnk1 and Mnk2 . Although the role of eIF4E phosphorylation in mammalian cells has remained elusive , recent work in Drosophila has established that it is required for growth and development . Here, we demonstrate that a previously identified Drosophila kinase called Lk6 is the functional homolog of mammalian Mnk kinases. We generated lk6 loss-of-function alleles and found that eIF4E phosphorylation is dramatically reduced in lk6 mutants. Importantly, lk6 mutants exhibit reduced viability, slower development, and reduced adult size, demonstrating that Lk6 function is required for organismal growth. Moreover, we show that uniform lk6 expression rescues the lethality of eIF4E hypomorphic mutants in an eIF4E phosphorylation site-dependent manner and that the two proteins participate in a common complex in Drosophila S2 cells, confirming the functional link between Lk6 and eIF4E. This work demonstrates that Lk6 exerts a tight control on eIF4E phosphorylation and is necessary for normal growth and development.

KW - Amino Acid Sequence

KW - Animals

KW - Base Sequence

KW - Blotting, Western

KW - Body Weights and Measures

KW - Cells, Cultured

KW - Drosophila/genetics

KW - Drosophila Proteins

KW - Eukaryotic Initiation Factor-4E/metabolism

KW - Female

KW - Gene Expression

KW - Immunoprecipitation

KW - Larva/growth & development

KW - Mitogen-Activated Protein Kinase Kinases/genetics

KW - Molecular Sequence Data

KW - Mutagenesis

KW - Ovary/metabolism

KW - Phenotype

KW - Phosphorylation

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Sequence Alignment

KW - Sequence Analysis, DNA

KW - Transfection

U2 - 10.1016/j.cub.2004.12.037

DO - 10.1016/j.cub.2004.12.037

M3 - Journal article

C2 - 15649359

SN - 0960-9822

VL - 15

SP - 19

EP - 23

JO - Current Biology

JF - Current Biology

IS - 1

ER -