The Long Journey from Phosphotyrosine to Phosphohistidine, and New Cancer Targets
Tyrosine phosphorylation of mammalian cell proteins was discovered 40 years ago, and this previously unsuspected modification proved to play key roles in many cellular processes, including growth factor signaling, cell shape and movement, and cell cycle progression, as well as being a driver of many types of cancer. In this lecture, the speaker will review the history of the discovery, and how this led to development of a large number of selective tyrosine kinase inhibitors (TKIs) for treatment of cancer and other diseases – currently, 37 TKIs have been approved for clinical use.
Histidine phosphorylation of proteins is poorly characterized in mammalian systems. Using monoclonal antibodies that selectively recognize the two phosphohistidine (pHis) isoforms, the speaker and his research group have carried out phosphoproteomic surveys for pHis-containing proteins suggests that this previously “hidden phosphoproteome” may be quite large, approaching the level of tyrosine phosphorylation. They have also collaborated with Michael HALL (Biozentrum, University of Basel) to show that pHis levels are elevated in liver tumors in a mouse model, as well as in human hepatocellular carcinoma (HCC) tumor tissue. The increase in histidine phosphorylation is due to reduced levels of the LHPP pHis phosphatase in tumor tissue. This suggests that the LHPP pHis phosphatase serves a tumor suppressor in HCC, and that histidine phosphorylation can act as a cancer driver, and can potentially be targeted as a new therapeutic approach.
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with few treatment options. They have identified leukemia inhibitory factor (LIF), a stem cell cytokine, as a key paracrine factor, secreted mainly by activated stromal cells (PSCs) in the tumor, known as pancreatic stellate cells (PSCs), that acts on the tumor cells to maintain a stem cell-like population in PDAC tumors. LIF binds to a surface receptor on tumor cells and triggers tyrosine phosphorylation and activation of the STAT3 transcription factor. Blockade of LIF with a neutralizing mAb slows tumor progression and augments the efficacy of gemcitabine chemotherapy treatment to prolong survival in the KPC mouse model of pancreatic cancer. LIF levels are strongly elevated in both mouse and human pancreatic tumor tissue. LIF is also detected in serum from tumor-bearing mice and human PDAC patients, suggesting its use as a biomarker and as a therapeutic target. A clinical trial is underway to assess the potential of a humanized anti-LIF antibody in cancer therapy.
About the speaker
Prof. Tony Hunter received his PhD in Biochemistry from University of Cambridge in 1969 for his work on mammalian protein synthesis. He was a Research Fellow in the Department and a Postdoctoral Fellow at the Salk Institute for Biological Studies working on polyoma virus DNA replication. He rejoined the Salk Institute as an Assistant Professor in 1975 in the Molecular and Cell Biology Laboratory. He is currently the Renato Dulbecco Chair in Cancer Research, Director of the US National Cancer Institute-designated Salk Institute Cancer Center, and an American Cancer Society Professor in the Molecular and Cell Biology Laboratory at the Salk Institute for Biological Studies. He is also an Adjunct Professor in the Division of Biological Sciences at the University of California, San Diego.
In 1979, Prof. Hunter discovered that polyomavirus middle T antigen and the RSV v-Src oncoprotein both exhibit a previously unknown protein kinase activity that phosphorylates tyrosine. He has spent most of the last thirty years studying protein kinases and phosphatases, and the role of protein phosphorylation in cell growth, the cell cycle, and cancer. He received numerous awards for his work on tyrosine phosphorylation. His current efforts are aimed at elucidating how post-translational modification of proteins by phosphorylation, ubiquitylation, and sumoylation is used to regulate cell proliferation and cell cycle checkpoint activation in response to DNA damage.
Prof. Hunter is a Fellow of the UK Royal Society, an EMBO Associate Member of Excellence in the Life Sciences, a Member of the US National Academy of Sciences, the Institute of Medicine, and the American Philosophical Society, and a Fellow of the American Academy of Arts and Sciences and of the American Association for Cancer Research. To recognize his significant discovery towards cancer research, he was awarded the Royal Medal in Biological Sciences (2014), the Sjöberg Prize for Cancer Research (2017), the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research (2018) and the Tang Prize in Biopharmaceutical Science (2018).