Mechanisms of cell growth and malignant transformation regulated by protein phosphorylation and dephosphorylation

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We showed the followings through the studies on cell growth regulation with special interest in protein phosphorylation. 1. Tob (1) Tob functions as a tumor suppressor because #1: tob suppresses cell growth when overexpressed, #2: tob-deficient mice are prone to cancer, and #3: expression of tob mRNA is often suppressed in various human tumors. (2) Tob becomes phosphorylated by Erk1/2 upon growth factor stimulation, which results in the loss of anti-proliferative activity of Tob. (3) Tob participates in transcription regulation because #1: Tob associate with HDAC and suppresses transcription of the cyclin Dl gene, #2: Tob regulates BMP signaling through its interaction with Smads. Consequently, tob-deficient mice develop an osteopetrotic phenotype. #3: Tob complexes with the NOT transcription machinery that consists of at least 10 Cnot proteins (Cnot1-10). Among Cnot proteins Cnot7 interacts with RXRβ, and like RXRβ-deficient mice Cnot7-deficient mice are sterile because of Oligo-asthe … More no-teratozoospermia. (4) Tob shuttles between nucleus and cytoplasm. In the cytoplasm Tob associates with polyA binding protein and regulates translation of mRNA. 2. Tyosine phosphorylation (1) Cbl-c induces v-Src ubiquitination and degradation, and thereby suppresses v-Src-mediated malignant transformation. (2) Agonistic monoclonal antibody we produced activates receptor tyrosine kinase ALK on the surface of PC12 cells, and induces their proliferation and neuronal differentiation. (3) ALK utilizes SNT2 adaptor protein for cell signaling, which is relevant to malignant cell transformation by activated ALK. 3. M phase kinases (1) Overexpression of human homologs of drosophila tumor suppressor proteins LATS1/2 results in M phase arrest. (2) RNAi-mediated down-regulation of LATS2-interacting protein Ajuba induces inhibition of spindle formation and chromosome segregation. (3) Ajuba also negatively regulates Wnt signaling through its interaction with β-catenin. (4) Phosphorylation of chromokinesin Kid by Cdc2 is important for chromosome dynamics and M phase progression. These data contributes to deepening our understanding on cell growth regulation. Less