Michael Ohh

Michael received his PhD from the University of British Columbia under the supervision of Dr. Fumio Takei and advisor Dr. Connie Eaves at the Terry Fox Laboratory, BC Cancer Agency. He was then awarded the Medical Research Council and National Cancer Institute of Canada postdoctoral fellowship to train in the laboratory of Dr. William G. Kaelin Jr. at the Dana-Farber Cancer Institute and Harvard Medical School where he made landmark contributions to our fundamental understanding of the metazoan oxygen-sensing pathway. He is a recipient of Canadian Cancer Society Bernard and Francine Dorval Prize, Premier’s Research Excellence Award, and Canada Research Chair in Molecular Oncology. 

Research Synopsis

Role of tumour suppressors and oncoproteins in cancer biology

Cancer is a disease characterized by uncontrolled cell growth that can spread to other parts of the body. Our research mission is to elucidate the molecular mechanisms governing the function of two major cancer-associated proteins called von Hippel-Lindau (VHL) tumour suppressor protein and Rat Sarcoma (RAS) oncoprotein with the supposition that lessons learned would provide fundamental understanding of normal and cancer cell biology and lay the foundation for the development of rational anti-cancer therapies.

VHL in solid tumours

Oxygen is essential for eukaryotic life and inextricably linked to the evolution of multicellular organisms. Proper cellular response to changes in oxygen tension during normal development or pathological processes, such as heart disease and cancer, is regulated by the transcription factor called hypoxia-inducible factor (HIF).

Tumour cells are inevitably challenged with limited oxygen availability as the growth of the tumour mass surpasses the diffusional capacity of oxygen from the nearest blood vessel. To overcome this crisis, tumour cells initiate the hypoxic response to trigger various adaptive responses, including anaerobic metabolism, angiogenesis and increased production of oxygen-carrying red blood cells. This is accomplished by the stabilization of HIF, which escapes oxygen-dependent destructive targeting by VHL tumour suppressor-containing E3 ubiquitin ligase complex under hypoxia.

Clinically relevant is the observation that mutation or loss of VHL causes VHL disease, which is characterized by the development of tumours in multiple organs such as the brain, spinal cord, retina, inner ear, pancreas, adrenal gland, and kidney. Furthermore, the extent of HIF expression correlates with disease aggressiveness and patient prognosis across a wide range of tumours from breast, prostate, and colon to kidney cancer, underscoring the importance of the evolutionarily conserved oxygen-sensing pathway in oncogenesis.

RAS in cancer

Mutations in RAS and various other components of the RAS signaling pathway are among the most common genetic alterations in human cancers and have also been identified in several developmental syndromes such as Noonan syndrome, Costello syndrome and cardiofaciocutaneous syndrome.

The three human RAS oncogenes (H‐RAS, N‐RAS, and K‐RAS) encode highly related 188-189 amino acid proteins. They are canonical members of a large superfamily consisting of more than 150 cellular members of small monomeric GTPase proteins, which function as molecular switches in a number of signaling pathways that regulate vital cellular functions. RAS cycles between the inactive GDP and active GTP bound forms through conformational changes near the nucleotide-binding site.

Over the past few decades, it has become clear that the activity or the oncogenic potential of RAS is dependent on the non-receptor tyrosine kinase Src and phosphatase SHP2 to regulate essential cellular pathways for proliferation, differentiation and survival of eukaryotic cells. However, the precise molecular interplay between RAS, Src and SHP2 remains an outstanding question.

Understanding the molecular mechanisms governing RAS will provide invaluable insights into the fundamental processes in cell biology and the pathogenesis of many forms of human cancer as well as numerous developmental syndromes.

Research training and opportunities

Our research approach is multidisciplinary with focus on molecular biology and protein biochemistry.

The research environment is highly interactive with state-of-the-art equipment and facilities and is an excellent training ground for graduate students and postdoctoral fellows who wish to pursue a career in academia.

Past members have garnered competitive national and international scholarships and been recruited to prestigious institutions such as Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, Dana-Farber Cancer Institute, Genentech, Stanford, Yale, M.I.T., and Harvard.

Selected Publications

Taber CC, He W, Gasmi-Seabrook GMC, Hubert M, Ferens FG, Ikura M, Lee JE, Ohh M. Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain. eLife. 2025 Oct 20; 14:RP107121.

Time-resolved NMR detection of prolyl-hydroxylation in intrinsically disordered region of HIF-1α. He W, Gasmi-Seabrook GMC, Ikura M, Lee JE, Ohh M. Proc Natl Acad Sci USA. 2024 Sep 10;121(37):e2408104121. 

Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation. Kano Y, Gebregiworgis T, Marshall CB, Radulovich N, Poon BPK, St-Germain J, Cook JD, Valencia-Sama I, Grant BMM, Herrera SG, Miao J, Raught B, Irwin MS, Lee JE, Yeh JJ, Zhang ZY, Tsao MS, Ikura M, Ohh M. Nature Communications. 2019 Jan 15;10(1):224.

HIF2α-pVHL complex reveals broad genotype-phenotype correlations in HIF2α-driven disease. Tarade D, Robinson CM, Lee JE, Ohh M. Nature Communications. 2018 Aug 22;9(1):3359.

Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis. Bunda S, Burrell K, Heir P, Zeng L, Alamsahebpour A, Kano Y, Raught B, Zhang ZY, Zadeh G, Ohh M. Nature Communications. 2015 Nov 30;6:8859.

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Niemeyer CM, Kang M, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. Nature Genetics. 2010 Sep;42(9):794-800.

Regulation of endocytosis via the oxygen-sensing pathway. Wang Y, Roche O, Yan M, Finak G, Evans AJ, Metcalf JL, Hast BE, Hanna SC, Wondergem B, Furge KA, Irwin MS, Kim WY, Teh BT, Grinstein S, Park M, Marsden PA, Ohh M. Nature Medicine. 2009 Mar;15(3):319-24.

HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Kirscher MW, Asara JM, Lane WS, Kaelin WG Jr. Science. 2001 Apr 20;292(5516):464-8.

Ubiquitination of HIF requires direct binding to the beta-domain of the von Hippel-Lindau protein. Ohh M, Park CW, Ivan M, Hoffman MA, Kim T-Y, Huang LE, Pavletich N, Chau V, Kaelin WG Jr. Nature Cell Biology. 2000 Jul;2(7):423-7.

Honours and Awards

Richard G. Hegele Award for Excellence in Research and Innovation (2019)

LMP Award for Undergraduate Teaching (2006)