John Blenis, PhD
Department of Cell Biology, Harvard Medical School
Signal transduction: nutrient and energy sensing; disease; mTOR; PI3-kinase; Ras
Explore the diverse yet overlapping intracellular transmission signals propagated by cell surface receptors that respond to extracellular growth factors, environmental conditions, and other factors.
Convert knowledge gained from signal transduction research studies into diagnostic and therapeutic utility; work with companies searching for early stage discoveries that have enormous potential for treating and diagnosing a variety of serious diseases associated with significant morbidity and mortality.
The studies directed by Dr. Blenis are focused on signaling pathways that control key metabolic processes, such as cell growth and protein synthesis. Numerous enzymes that participate in these transmission circuits are now being pursued as druggable targets, including protein kinases, such as mTOR, PI3-kinase, and AKT. Frequent dysregulation of the Ras, PI3-kinase, and mTOR pathways is observed in cancer cells and cancer metastasis. Metastasis, the cause of most cancer-related mortality, appears to involve constitutively activated Ras signaling for many cancers. Moreover, dysregulated mTOR pathway signaling may underlie a variety of disorders, including neurodegenerative disease and diabetes. While interested in the basic biochemistry of these signaling mechanisms, including those related to the epithelial-to-mesenchymal transition that underlie the tumorigenic process for many epithelial cancers, the lab also has a keen interest in converting its insights into commercial applications, such as biomarkers or therapeutic targets. The lab is well-positioned to uncover basic mechanisms of intracellular signaling that will lay the foundation for future commercial applications.
Current Research Interests
- Study biochemical aspects of the predominant signal transduction circuits, the Ras, PI3K, and mTOR pathways, the integration of their signals (that is, “cross-talk”), and their role in sensing environmental fluctuations.
- Investigate how these signaling pathways modulate and coordinate cellular metabolic processes such as gene expression, pre-mRNA splicing and protein synthesis.
- Capitalize on the lab's in-depth knowledge of intracellular signaling to identify new biomarkers, as well as novel therapeutic targets for cancer, aging, neurodegenerative diseases, diabetes, and obesity.
- Study the biochemical mechanism of rapamycin inhibition of mTOR and the development of resistance.
- Explore the role of Ras/ERK/RSK signaling in cell survival, migration, and invasion during the epithelial-to-mesenchymal transition and its link to metastasis.
The Blenis laboratory has uncovered important biochemical mechanisms that coordinate extracellular cues, intracellular signaling pathways, and metabolic processes, such as gene expression and protein synthesis. The lab has researched the major signaling pathways, including the Ras/ERK/RSK and the PI3-K/Akt signaling circuits. Moreover, the lab has performed extensive analyses of mammalian target of rapamycin (mTOR), a checkpoint kinase that deftly integrates signals emanating from growth factors and environmental conditions (for example, nutrient status) to guide cellular decisions.
The lab elucidated important aspects of the mTOR functional repertoire, focusing on the executive decision making process that mTOR exercises over the exon junction complex (EJC) and mRNA splicing. Because protein synthesis is an energy intensive process, numerous controls must tightly regulate protein translation, and mTOR is a key “middleman” in this regulatory circuit. In the mRNA surveillance process mediated by the EJC, abnormal mRNAs are filtered out prior to the initiation of translation, thus preventing translation of unwanted mRNA species. Translation initiation is promoted by mTOR-mediated signaling, and the lab demonstrated that mTOR, and a ribosomal kinase, link the integrity of protein translation with the EJC and pre-mRNA splicing via proteins, such as SKAR. These findings illuminate an important regulatory control mechanism that coordinates RNA processing and protein translation. Other data have uncovered an important element that titrates the output from certain signal transducing pathways. The lab has discovered that Ran binding protein 3, a regulator of the nuclear uptake factor Ran, is tightly modulated by phosphorylation, a modification carried out by signaling proteins such as RSK and Akt.