Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane.
The PKB (protein kinase B, also called Akt) family of protein kinases plays a key role in insulin signaling, cellular survival, and transformation. PKB is activated by phosphorylation on residues threonine 308, by the protein kinase PDK1, and Serine 473, by a putative serine 473 kinase. Several protein binding partners for PKB have been identified. Here, we describe a protein partner for PKBalpha termed CTMP, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of PKBalpha at the plasma membrane. Binding of CTMP reduces the activity of PKBalpha by inhibiting phosphorylation on serine 473 and threonine 308. Moreover, CTMP expression reverts the phenotype of v-Akt-transformed cells examined under a number of criteria including cell morphology, growth rate, and in vivo tumorigenesis. These findings identify CTMP as a negative regulatory component of the pathway controlling PKB activity.
Maira
S M
SM
Friedrich Miescher Institute, Post Office Box 2543, CH-4002 Basel, Switzerland., Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
Galetic
I
I
Brazil
D P
DP
Kaech
S
S
Ingley
E
E
Thelen
M
M
Hemmings
B A
BA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism*; D048429:Cell Size; D004789:Enzyme Activation; D016762:Genes, fos; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000209:etiology; D051058:Oncogene Protein v-akt; D010170:Palmitoyl-CoA Hydrolase; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013869:Thiolester Hydrolases; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007328:Insulin; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic; C076715:pervanadate; D014638:Vanadates; D007334:Insulin-Like Growth Factor I; C494918:AKT1 protein, human; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C437985:THEM4 protein, human; D013869:Thiolester Hydrolases; C527670:CTMP protein, mouse; D010170:Palmitoyl-CoA Hydrolase