IUBMB Life, 53: 1, 2002Copyright c© 2002 IUBMB1521-6543/02 $12.00 + .00

Review Article

Phosphatases Fight Back

Christina MitchellDepartment of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia

Growth factor-induced protein tyrosine phosphorylation in-duces a diverse array of signaling pathways, including genera-tion of phosphoinositide 3-kinase (PI 3-kinase) signals that bindand, in turn, activate effector proteins leading to cellular re-sponses that include cell growth, proliferation, differentiation,migration, cytoskeletal organization, metabolism, endocytosis,and vesicular trafficking. Many recent studies have concentratedon the pathways that either terminate, or modify growth factor-induced cellular activation. These include the protein tyrosinephosphatases, a large and structurally diverse family of enzymesthat can either antagonize or potentiate protein tyrosine kinasesignaling and the lipid phosphatases that terminate or modu-late PI 3-kinase signals. A unifying theme linking these di-verse enzyme families is presented in the accompanying fourreviews. These protein and lipid phosphatases, despite signifi-cant differences in their substrates that may be either proteinsor phospholipids or both, are characterized by the presence ofthe signature motif HC(X)5R. In the first review, Tony Tiganisdiscusses the role the protein tyrosine phosphatases play in reg-ulating epidermal growth factor-induced signaling events. The

Received 24 October 2001; accepted 24 October 2001.Address correspondence to Christina Mitchell, Dept. of Biochem-

istry and Molecular Biology, Monash University, P.O. Box 13D,Victoria 3800, Australia.

following review by Whisstock and colleagues describes therecent intriguing discovery of the catalytic mechanism of theinositol polyphosphate 5-phosphatases. Many members of thisextensive enzyme family contain two catalytic domains, com-prising a “Sac-1-like domain,” which contains a C(X)5R motifand a 5-phosphatase domain that hydrolyzes 5-position phos-phates from both inositol phosphate and phosphoinositide sig-naling molecules. Until very recently, the mechanism of ac-tion of the latter catalytic domain was not understood. Twostudies, one using a bioinformatics approach and the secondusing X-ray crystallography, have demonstrated the surprisingdiscovery that the 5-phosphatases belong to a larger extensivefamily of proteins that share the same catalytic mechanism ofaction: the Apurinic/Apyrimidinic base excision repair endonu-cleases. In the third review, the functional roles of the5-phosphatases in regulating many cellular events are describedin detail; and in the final review by Nandurkar and Huysmans,the recent exciting discoveries linking PtdIns 3-P and the myo-tubularin family of lipid phosphatases with human myopathiesare presented.

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