Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions.
PTEN phosphatase is one of the most commonly targeted tumor suppressors in human cancers and a key regulator of cell growth and apoptosis. We have found that PTEN is cleaved by caspase-3 at several target sites, located in unstructured regions within the C terminus of the molecule. Cleavage of PTEN was increased upon TNFalpha-cell treatment and was negatively regulated by phosphorylation of the C-terminal tail of PTEN by the protein kinase CK2. The proteolytic PTEN fragments displayed reduced protein stability, and their capability to interact with the PTEN interacting scaffolding protein S-SCAM/MAGI-2 was lost. Interestingly, S-SCAM/MAGI-2 was also cleaved by caspase-3. Our findings suggest the existence of a regulatory mechanism of protein stability and PTEN-protein interactions during apoptosis, executed by caspase-3 in a PTEN phosphorylation-regulated manner.
Torres
Josema
J
Instituto de Investigaciones Citológicas, Amadeo de Saboya 4, Valencia 46010, Spain.
Rodriguez
Joe
J
Myers
Michael P
MP
Valiente
Miguel
M
Graves
Jonathan D
JD
Tonks
Nicholas K
NK
Pulido
Rafael
R
D030301:Activin Receptors, Type II / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D047390:Casein Kinase II; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D051528:Guanylate Kinases; D006801:Humans; D007668:Kidney / Q000166:cytology; D016296:Mutagenesis; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C114103:Magi2 protein, rat; D011506:Proteins; D025521:Tumor Suppressor Proteins; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D030301:Activin Receptors, Type II; D051528:Guanylate Kinases; C485777:MAGI2 protein, human; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases