Jose M. Orozco
Researcher trained in David Sabatini's laboratory at the Whitehead Institute and MIT who showed that mTORC1 senses glucose through the glycolysis metabolite DHAP
Harvard/MIT MD-PhD Program; PhD student in the Sabatini laboratory, Whitehead Institute and MIT Department of Biology (papers 2014–2021; at the time of the studies) · undergraduate research in Erin Cram's lab, Northeastern University
Lab lineagetrained under David M. Sabatini →
Portrait: MIT Department of Biology
Jose Orozco is a co-author of four Atlas papers from David Sabatini's laboratory at the Whitehead Institute that mapped how mTORC1, the growth-control complex, learns what nutrients a cell has. Sestrin proteins bind the GATOR2 complex to dampen amino acid signalling (CHA2014). A complex named KICSTOR holds the GATOR1 brake at the lysosome so that nutrients can control mTORC1 (WOL2017). A protein named SAMTOR senses S-adenosylmethionine, a molecule made from the amino acid methionine (GU2017), which links mTORC1 to diet in a way that may matter for why methionine restriction affects aging. And genome-wide CRISPR screens showed that the kinases AMPK and HRI relay mitochondrial problems to mTORC1 (CON2021). These are laboratory studies, mostly in cultured cells.
Orozco's own first-author paper, in Nature Metabolism in 2020, answered a question the field had left open: how mTORC1 knows that glucose is present, separately from the energy sensor AMPK. Working in human cells engineered to lack AMPK, the team traced the signal to dihydroxyacetone phosphate (DHAP), a molecule made partway through glycolysis. DHAP is also a starting material for making fats, a process that mTORC1 controls, which gives a reason for the cell to watch it.
Orozco came to the work through the Harvard/MIT MD-PhD Program, which trains doctors who also do research. After two years at Harvard Medical School, Orozco started a PhD as an MIT Biology graduate student in Sabatini's lab at the Whitehead Institute. Before medical school, Orozco studied at Northeastern University and did research there in Erin Cram's lab on the roundworm C. elegans. In a Whitehead Institute podcast recorded during the fifth year of the PhD, Orozco described the DHAP finding and said the plan was to finish the medical degree without further clinical training and to build a research career. No later position could be confirmed, so the affiliation shown is the one on the Atlas papers.
Milestones in the Atlas
A selection, not a full bibliography: only papers that meet the Atlas inclusion criteria.
| Year | Evidence | Study |
|---|---|---|
| 2014 | M | The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1 CHA2014 Co-author of the study showing that Sestrins bind GATOR2 to restrain amino acid signalling to mTORC1. |
| 2017 | M | KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1 WOL2017 Co-author of the study showing that KICSTOR recruits GATOR1 to the lysosome. |
| 2017 | M | SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway GU2017 Co-author of the study identifying SAMTOR as an S-adenosylmethionine sensor for mTORC1. |
| 2021 | M | Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction CON2021 Co-author of the CRISPR screen study showing that AMPK and HRI relay mitochondrial dysfunction to mTORC1. |
Co-authors in the Atlas 15
People with a profile here who share at least one study with Jose M. Orozco.
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- David M. Sabatini 4 shared studies Identified mTOR (as RAFT1) in 1994. His lab then mapped much of the machinery around it: raptor and rictor at the core of mTORC1 and mTORC2, the Rag–Ragulator system that docks mTORC1 on the lysosome, and the sensors that detect leucine, arginine and SAM
- Kendall J. Condon 3 shared studies Ran genome-wide CRISPR screens revealing how mitochondrial stress signals to mTORC1
- Sonia M. Scaria 3 shared studies Contributed, as an MIT undergraduate in the Sabatini lab, to the discovery of CASTOR1 as the arginine sensor and SAMTOR as the SAM sensor of the mTORC1 pathway
- Lynne Chantranupong 2 shared studies Showed as a Sabatini-lab graduate student that the Sestrins act through GATOR2 to regulate amino-acid signalling to mTORC1. She then discovered the CASTOR proteins, the cell's arginine sensors for the pathway
- Rachel L. Wolfson 2 shared studies Identified Sestrin2 as the direct leucine sensor of the mTORC1 pathway as a Sabatini-lab MD-PhD student. She also co-discovered KICSTOR, the complex that recruits GATOR1 to the lysosome
- Robert A. Saxton 2 shared studies Solved, as a Sabatini-lab graduate student, the structures of the leucine sensor Sestrin2 and the arginine sensor CASTOR1, showing how each one grips its amino acid. He also co-wrote a widely cited 2017 review of mTOR signalling with David Sabatini
- Steven P. Gygi 2 shared studies Mass-spectrometry scientist whose Harvard lab builds large-scale proteomics methods, including the BioPlex human protein-interaction map, and contributed proteomics to the discoveries of the CASTOR and SAMTOR nutrient sensors
- Xin Gu 2 shared studies Cell biologist who discovered SAMTOR, the sensor that lets mTORC1 read the methyl donor SAM, as a PhD student at MIT, and who now leads a lab at Dana-Farber and Harvard Medical School studying ubiquitin-independent protein destruction by the midnolin-proteasome pathway
- Eric Spooner Manager of the Whitehead Institute's Proteomics Core Facility, whose mass spectrometry work identified proteins in complexes for many Whitehead studies, including two on amino acid sensing upstream of mTORC1
- Grace Y. Liu Wrote with David Sabatini a major 2020 review of mTOR in nutrition, growth and ageing, and in the Sabatini lab studied how mTORC1 senses nutrients such as serine
- Gregory A. Wyant Showed that the lysosomal protein SLC38A9 exports leucine and other essential amino acids out of the lysosome, letting cells grow on proteins they have taken up and broken down there
- J. Wade Harper Co-discovered the F-box motif that links substrates to SCF ubiquitin ligases, and co-leads with Steven Gygi the BioPlex protein-interaction map, which contributed to the discoveries of the CASTOR and SAMTOR nutrient sensors
- Kuang Shen Solved, as a Sabatini-lab postdoc, cryo-EM structures of GATOR1 and of the FLCN–FNIP2–Rag–Ragulator complex, two switches that set mTORC1 activity. His UMass Chan lab studies the structural basis of nutrient sensing
- Liron Bar-Peled Showed as a Sabatini-lab graduate student that Ragulator switches the Rag GTPases on, acting as their GEF. He also discovered GATOR1 and GATOR2; GATOR1 switches the Rags off and its genes are mutated in some cancers
- Monther Abu-Remaileh Worked out how to isolate lysosomes fast enough to measure what is inside them, and found that mTOR controls what gets out
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