John Kendrew Lecture to be given by Tony Hunter

Hunter_2014_Photo
Credit: The Salk Institute

Tony Hunter will give the delayed John Kendrew Lecture 2015 on Wednesday 25th May 2016 at 15.00 in the LMB’s Max Perutz Lecture Theatre.

The title of the lecture is ‘Post-translational regulation of cell signalling’. The event is open to anyone in the local area who is interested in attending.

Tony made the seminal discovery, more than three decades ago, that the attachment of phosphate molecules to tyrosine, one of the 20 amino acids in proteins, allows cells to control when key proteins are on standby and when they are active. In cancers, he went on to show that growth was switched into an always-on mode as a result of overabundance of this type of phosphate modification. Since then, his lab has led the field in understanding how chemical additions to proteins control the cell cycle and growth.

Tony received his B.A. in 1965 from the University of Cambridge, and his Ph.D. in 1969 for work on mammalian protein synthesis under Asher Korner in the Department of Biochemistry, University of Cambridge. He was a Research Fellow in the Department from 1968-1971, and a postdoctoral fellow at the Salk Institute from 1971-1973 working under Walter Eckhart on polyoma virus DNA replication. He rejoined the Salk Institute as an Assistant Professor in 1975 in the Molecular and Cell Biology Laboratory, where he is currently the Renato Dulbecco Chair in Cancer Research and Deputy Director of the Salk Institute Cancer Center.

Lecture abstract:

 Post-translational modification (PTM) is a means of increasing the complexity of the proteome, and reversible PTMs are commonly used in the transmission of signals within cells in response to external stimuli. Protein phosphorylation is involved in the majority of cellular processes and thousands of distinct phosphorylation events can be detected in a single cell type. The human kinome comprises >530 protein kinases of which 480 are typical eukaryotic protein kinases (ePKs), and the remainder are atypical protein kinases (aPKs); the majority are Ser/Thr kinases, but there are 90 Tyr kinases. In addition to Ser, Thr and Tyr, six other amino acids can be phosphorylated, including the three basic amino acids, His, Lys and Arg. Histidine phosphorylation of proteins is becoming increasingly relevant as a regulatory mechanism, and two aPKs, NME1 and NME2, can reportedly phosphorylate histidine in target proteins. To study global histidine phosphorylation events we generated monoclonal antibodies (mAbs) to non-cleavable 1-pHis and 3-pHis analogues, and are using these mAbs to study histidine phosphorylation in normal and transformed cells and in metastasis. By using immobilised mAbs for affinity purification of pHis proteins from 293 cells, we have identified ~800 proteins that bound selectively under denaturing conditions, and putatively contain 1-pHis (~250) or 3-pHis (~160). We have begun to characterise some of these pHis proteins, and develop MS methods to pinpoint the exact sites of His phosphorylation. Immunostaining of HeLa cells and primary macrophages with anti-1-pHis mAbs revealed staining on the outside of phagocytic vesicles; immunostaining of proliferating HeLa cells with anti-3-pHis mAbs showed a striking pattern in mitotic cells, with strong staining of spindle poles (and centrosomes in interphase cells) and the midbody, suggesting that phosphorylation of His at the 3-position may regulate some aspects of the mitotic process.

Aberrant protein phosphorylation plays a role in many human diseases, and particularly in cancer. In this connection, we have studied the phenotypes of several newly identified cancer-associated protein kinase mutations, and have found, surprisingly, that mutations in DAPK3, MLK4, and protein kinase C are all loss of function, implying that they act as tumour suppressors. The tumour microenvironment, which comprises many different stromal cells types in addition to tumour cells, is now recognised as playing a key role in the development of cancer. Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, and PDAC has an unusually dense stromal matrix surrounding the tumor cells. To better understand the relationship between stromal cells and tumour cells in PDAC, we have investigated the crosstalk between pancreatic cancer cells and pancreatic stromal cells, known as stellate cells, by proteomic analysis of secreted proteins and of tyrosine phosphorylation events induced by secreted proteins in both cell types. We have found that LIF and IL-6 cytokines secreted by stellate stromal cells elicit JAK/STAT3 signaling in the tumour cells, and that PDGF secreted by the tumour cells in turn activates the stellate cells, thus setting up a reciprocal paracrine loop that could in principle be targeted for PDAC therapy. As a proof of principle that this is possible, using a mouse model of PDAC, we have found that administration of a neutralising anti-LIF mAb prolongs survival when used in combination with gemcitabine.

Background information:

The John Kendrew Lecture is named in honour of LMB Nobel Laureate John Kendrew. It is one of a series of named lectures organised by the LMB to be given by eminent scientists from around the world.

John Kendrew was born in Oxford on 24th March 1917. He studied chemistry at Trinity College, Cambridge and graduated in 1939. During World War II he worked on radar for the Air Ministry Research Establishment. In 1946 he returned to Cambridge and joined Max Perutz at the MRC ‘Unit for Research on the Molecular Structure of Biological Systems’ (now the MRC Laboratory of Molecular Biology) where his research focused on protein structure and the X-ray analysis of myoglobin. In the 1960′s John jointly founded the European Molecular Biology Organisation (EMBO) and helped create and was first Director of the European Molecular Biology Laboratory (EMBL). He also founded and was Editor in Chief of the Journal of Molecular Biology. From 1981-1987 he was President of St John’s College, Oxford. He died in Cambridge on 23rd August 1997.

Further references:

Tony Hunter group page
Poster for the John Kendrew Lecture
John Kendrew biography