Identification of Intracellular Signaling Pathways Regulated by the TAO Family of Mammalian STE20p Kinases

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Title: Identification of Intracellular Signaling Pathways Regulated by the TAO Family of Mammalian STE20p Kinases
Author: Raman, Malavika
Abstract: TAO1 , 2 and 3 are a sub -family of mammalian Ste20p protein kinases . They have been shown to regulate activation of p38 MAPK by phosphorylating and activating MEK3 and 6 . Little is known about the precise cellular roles for these TAO protein kinases , or whether they function together or individually within the cell . Recently , genome -wide screens have identified these protein kinases as important mediators of vital cellular processes such as proliferation and apoptosis . Determining the mechanisms that govern the activity of these protein kinases and the pathways that utilize them is of utmost importance for understanding important aspects of cell signaling . My research focused on determining physiological stimuli that activated TAO protein kinases and the consequence of this activation on downstream signaling . This approach , in conjunction with two -hybrid screening led to the elucidation of two pathways that utilized TAO kinases . TAO2 interacted with Gas and Gbeta gamma subunits in yeast two -hybrid screens . TAO2 phosphorylated Gas on threonine 9 in the N -terminus , and this phosphorylation was inhibited when the a subunit was activated by GTPgamma S . TAO2 also interacted with Gbeta gamma in detergent -soluble membrane extracts from cells . At present , the biological significance of this interaction is unclear . I also showed that TAO1 , 2 and 3 are activated significantly by agents that damage DNA . The kinetics of activation mirrors that of p38 MAPK . I subsequently demonstrated that over -expression of kinase -deficient TAOs inhibited the activation of p38 by UV and hydroxyurea . The relative contribution of MEK3 and 6 in the activation of p38 by these agents was also determined . Knockdown of TAO 1 -3 protein levels by siRNA oligonucleotides against these protein kinases also mimicked the dominant -negative results . TAO kinases interact with one another and p38 and this may be one manner in which signaling is made selective and efficient . The UV -induced G2 /M checkpoint is diminished when TAO kinase expression levels are reduced by siRNA . Finally we show that TAOs may be substrates of the ataxia telangiectasia mutated (ATM ) and ATM and Rad50 -related (ATR ) DNA damage kinases , as activation of TAO2 is diminished in cells from a patient with AT , which do not express ATM . These findings show that TAO kinases regulate critical events in cell -cycle arrest by DNA damage by acting as intermediates in p38 activation by ATM /ATR .
URI: http : / /hdl .handle .net /2152 .5 /501
Date: 2006-05-16

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Identification of Intracellular Signaling Pathways Regulated by the TAO Family of Mammalian STE20p Kinases. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /501 .

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