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Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane

S M Maira1, I Galetic, D P Brazil

  • 1Friedrich Miescher Institute, Post Office Box 2543, CH-4002 Basel, Switzerland., Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.

Science (New York, N.Y.)
|October 13, 2001
PubMed

Insights

Carboxyl-terminal modulator protein (CTMP) binds to protein kinase B alpha (PKBalpha) and inhibits its activity. CTMP expression reverses cancer cell phenotypes, identifying it as a negative regulator of PKB signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Protein kinase B (PKB), also known as Akt, is a crucial kinase involved in insulin signaling, cell survival, and transformation.
  • PKB activation requires phosphorylation at specific residues, notably threonine 308 (by PDK1) and serine 473 (by a serine 473 kinase).
  • Several protein partners of PKB have been identified, suggesting complex regulatory mechanisms.

Purpose of the Study:

  • To identify and characterize novel protein binding partners of PKBalpha.
  • To investigate the functional role of the identified binding partner in PKBalpha activity and cellular transformation.

Main Methods:

  • Identification of CTMP (carboxyl-terminal modulator protein) as a specific binding partner for PKBalpha.
  • Analysis of CTMP binding to the carboxyl-terminal regulatory domain of PKBalpha at the plasma membrane.
  • Assessment of CTMP's effect on PKBalpha phosphorylation at serine 473 and threonine 308.
  • Evaluation of CTMP's impact on the phenotype of v-Akt-transformed cells, including morphology, growth rate, and tumorigenesis.

Main Results:

  • CTMP specifically binds to the carboxyl-terminal regulatory domain of PKBalpha at the plasma membrane.
  • Binding of CTMP inhibits PKBalpha activity by reducing phosphorylation at both serine 473 and threonine 308.
  • CTMP expression effectively reverts the transformed phenotype of v-Akt-transformed cells, impacting morphology, growth, and tumorigenesis.

Conclusions:

  • CTMP is identified as a novel negative regulatory protein for PKBalpha.
  • CTMP modulates PKBalpha activity through direct binding and inhibition of key phosphorylation events.
  • CTMP plays a significant role in controlling cellular transformation, suggesting its potential as a therapeutic target in cancer.

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