Genome-wide survey of protein kinases required for cell cycle progression

Abstract

Cycles of protein phosphorylation are fundamental in regulating the progression of the eukaryotic cell through its division cycle. Here we test the complement of Drosophila protein kinases (kinome) for cell cycle functions after gene silencing by RNA-mediated interference. We observed cell cycle dysfunction upon downregulation of 80 out of 228 protein kinases, including most kinases that are known to regulate the division cycle. We find new enzymes with cell cycle functions; some of these have family members already known to phosphorylate microtubules, actin or their associated proteins. Additionally, depletion of several signalling kinases leads to specific mitotic aberrations, suggesting novel roles for familiar enzymes. The survey reveals the inter-digitation of systems that monitor cellular physiology, cell size, cellular stress and signalling processes with the basic cell cycle regulatory machinery.

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…Knock-down of Lats, on the other hand, resulted in an increase of cells in the G1 phase of the cell cycle. The authors speculated that Lats might accelerate progression through G2/M, thereby shifting more cells into G1 [59]. In light of the finding that Lats can inhibit CDK1 during mitosis in human cells and flies [25], this interpretation might be correct.…”

“…In 2004, Bettencourt-Dias and colleagues screened the Drosophila kinome for cell cycle functions by RNA-mediated interference (RNAi), thereby revealing that Hippo and Lats are required for normal cell cycle progression [59]. Depletion of Hippo caused mitotic spindle abnormalities, suggesting that Hippo plays a role in mitotic progression.…”

Developmental roles of tribbles protein family members

“…In some tissues, Trbl blocks cell proliferation: (1) in the eye, Trbl misexpression enhanced while conversely, trbl mutants suppressed, misexpression of Dwee1, a kinase that phosphorylates and blocks Cdc2/Cdk activity (Price et al, 2002); (2) in S2 cells, RNAi knockdown of Trbl increases the number of S2 cells in G1 with no effect on cell size (Bettencourt-Dias et al, 2004); and (3) trbl mutations suppress eye overgrowth phenotypes resulting from overexpression of the Jak/Stat pathway ligand Unpaired (Mukherjee et al, 2006).…”

LKB1; linking cell structure and tumor suppression

“…Another attractive possibility is that the polarity defects accompanying LKB1 inactivation could contribute to tumorigenesis by impairing genomic stability as has been shown in Drosophila (Bonaccorsi et al, 2007;Lee et al, 2007). Large-scale RNAi screens in Drosophila cell lines suggest that Lkb1 and AMPK are required for normal cellular division (Bettencourt-Dias et al, 2004). It will be of significant interest to determine whether chromosomal aberrations are associated with LKB1 deficiency in mammalian cells.…”