Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin.
The bipartite transcription factor beta-catenin/TCF (cat/TCF) has been recognized as the major effector of the Wnt signaling pathway for more than a decade, and its over-activation has been associated with malignancy such as colon and breast cancer. Extensive examination in different cell lineages has shown that the activity of cat/TCF can be stimulated by mechanisms other than via the Wnt glycoproteins, including the stimulation of beta-cat nuclear translocation and enhanced binding of cat/TCF to the Wnt target gene promoters by insulin and insulin-like growth factor-1 (IGF-1). In addition, the heterotrimeric G proteins of the G(12) subfamily can interact with the cytoplasmic domain of cadherins, resulting in the release of the transcriptional activator beta-cat. Furthermore, certain peptide hormones may stimulate cat/TCF-mediated gene transcription via activation of their corresponding G-protein coupled receptors. Recently, the serine/threonine kinase GSK-3 has been recognized to coordinate with AMP activated protein kinase (AMPK) in phosphorylation and activation of TSC2, the major component of the tumor suppressor complex TSC1/2. Thus, Wnt activation can stimulate protein translation via GSK-3 and TSC1/2 inactivation, followed by mTOR activation. Finally, beta-cat also functions as a pivotal molecule in defense against oxidative stress via serving as a partner of forkhead box O (FOXO) transcription factors. Thus, FOXO proteins, which mainly mediate aging and stress signaling, and TCF factors, which mainly mediate developmental and proliferation signaling, compete for a limited pool of free beta-cat. Insulin and growth factors, on the other hand, control the balance between TCF- and FOXO-mediated gene transcription via phosphorylation and nuclear exclusion of FOXO proteins. These observations provide new insight to understand how Wnt, insulin/growth factors, and FOXOs are involved in versatile physiological events and the development and progression of various human diseases.
Jin
Tianru
T
Department of Medicine, University of Toronto, Canada. tianru.jin@utoronto.ca
George Fantus
I
I
Sun
Jane
J
D000818:Animals; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases