The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.

http://science.sciencemag.org/content/sci/307/5712/1098.full.pdf

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

mTOR Signaling in Growth, Metabolism, and Disease.

THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways1,2. FKBP12–rapamycin inhibits progression through the Gl phase of the cell cycle in osteosarcoma3, liver4, 5 and T cells6, 7 as well as in yeast8 and interferes with mitogenic signalling pathways that are involved in Gl progression9, 10 namely with activation of the protein p70S6k (refs 5,11–13) and cyclin-dependent kinases3, 14–16. Here we isolate a mammalian FKBP–rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae8, 17, 18. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP–rapamycin complex directly17, 19 these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases17–20.

Kazuo ichikawa

Papers

A mammalian protein targeted by G1-arresting rapamycin–receptor complex