Peter Parker: Projects

In cancer, the cell autonomous behaviours of tumour cells are driven through diverse genetic (somatic) and epigenetic changes that confer competitive growth and survival properties within and beyond the tumour niche. Of the protein variants found in cancers, protein kinases are disproportionately represented, reflecting likely driver functions.

Understanding the physiological and pathophysiological regulatory networks of these kinases provides important insight into the liabilities and opportunities for intervention. Among this regulatory gene super-family are the protein kinase C (PKC) family, comprising a group of four closely related branches of the AGC kinase class.

The laboratory is interested in the roles of the PKC family in normal and transformed contexts, informing on and collaborating in opportunities for drug development, and deriving fundamental mechanistic insights that inform laterally on other cancer instructive regulatory networks.

aPKC in polarity and proliferation

There is a well-established role for atypical PKCs (aPKC) in supporting cell polarity and a less well characterised role in promoting proliferation and survival. The tumour-associated loss of polarity in advanced disease, juxtaposed to the characteristic gain of proliferation, demands a better understanding of aPKC action in positively supporting these distinctive properties. For this purpose, and in parallel with biomarker identification in a drug discovery program (collaboration with Cancer Research Technology, CRT), we have identified new aPKC substrates that inform on these aPKC functions.

In the cell polarity context we have established a pattern of threshold behaviour of aPKCι: too little or too much aPKCι disrupts the formation of acini structures in a 3D model; partially suppressing aPKCι activity by titration of an aPKC-specific inhibitor rescues an amorphous morphology in a mutant Ras transformed derivative (Figure 1). The molecular details of the functional relationship between mutant Ras and aPKCi are subject to ongoing studies as is our analysis of Ras driven GEMMs and aPKC intervention.

Figure 1

Figure 1. PKCι controls normal morphology and polarity. Manipulation of PKCι activity through gain of function and loss of function mutations influences the patterns of MDCK cell acini formation in 3D culture, as indicated in the scheme. Loss typically leads to divisions not in the appropriate plane (multilumen phenotype; grey centres), while gain of function at a moderate level increases proliferation with retention of organisation (single large lumen). At an elevated level of functional upregulation, organisation is lost all together (amorphous structure). This latter state can be induced by Ras-dependent transformation in a manner suppressed by small molecule inhibitors of PKCι. (Click to view larger image)

Functionally, the input to the formation of normal polarised acini in 3D culture requires the aPKCι kinase domain motif spanning arginine 471 to arginine 474 ("RIPR" motif; collaboration with the Structural Biology Group). Mutation of the arginine residues in this motif (AIPA mutant) results in a variant aPKCι that can no longer support normal acini growth in 3D culture. Of the rare mutations of aPKCι found in cancer R471 mutation is a repeated event. The R471C mutant like the experimental AIPA mutant is unable to confer normal acini growth in 3D culture. Mechanistically, integrity of the RIPR motif is required for the binding of a subset of aPKCι interacting partners/substrates, including LLGL1,2 and MyosinX but not Par3,6 and Sequestosome1. How the repertoire of RIPR motif interactors contribute to polarity and morphology and the relevance to invasion (collaboration with Erik Sahai) and advanced disease comprise ongoing objectives.

PKCε control of cell cycle

Some of our earlier work on PKCε evidenced its role in completing cytokinesis in particular tumour cell models. Further analysis has demonstrated that this property is related to earlier cell cycle stress that is itself influenced by PKCε action.Specifically we have shown that sister chromatid non-disjunction at the metaphase-anaphase transition triggers a PKCε dependent delay in anaphase entry.

We are employing various molecular, chemical biology, cellular and imaging approaches ex vivo and in vivo to better understand the role PKCε plays both at this metaphase-anaphase transition and at cytokinesis. Molecular analysis of the behaviour of the spindle assembly checkpoint (SAC) and the No-Cut pathway are both providing detailed insights into PKCε action. How and when these processes are engaged, and what distinguishes the normal from the transformed state, comprise additional avenues of work that will inform on possible PKCε interventions.

PKN proteins in cancer

The PKN class of PKC family proteins are Rho and Rac responsive protein kinases, sharing regulatory inputs with a broad collection of signalling proteins that typically have been neglected in considering Rho family responses.

In the context of cancer, there is evidence indicating specific PKN isoform action in particular tumours, this includes a role for PKN3 in invasive behaviour in advanced prostate cancer. The rather specific role for this isoform is not reflected in other ex vivo migratory contexts and our evidence indicates that different PKN isoforms contribute to migration in different cell types through non-redundant regulatory inputs. The extent to which unique and redundant actions characterise the PKN isoforms is being pursued in knock-out and conditional knock-out models under physiological and pathophysiological conditions.

PKC properties and the wider signalling network

We have established the importance of nucleotide pocket occupation driving conformational change in the PKC family. The generality of this normally ATP-driven behaviour has broad implications for kinases and pseudokinases and this has explained various anomalous behaviours associated with certain ATP-competitive inhibitors directed at other kinases. Conformational switches in kinases consequent to nucleotide binding, suggests that pseudokinases may not be simple 'inert' scaffolds/partners.

Amongst the family of pseudokinases, the EGF receptor family member HER3 is an important regulator in cancer. Work in collaboration with Professor Tony Ng (King's College London) is addressing the role and mechanisms of HER3 nucleotide pocket occupation (ATP/drug) and the consequent effects of oligomerisation and signal output.

Peter Parker

peter.parker@crick.ac.uk
+44 (0)20 379 61977

  • Qualifications and history
  • 1979 PhD in Biochemistry, Oxford, UK
  • 1979 MRC Postdoctoral Fellowship, Dundee, UK
  • 1982 Postdoctoral Fellow, Imperial Cancer Research Fund, UK
  • 1985 Laboratory Head, Imperial Cancer Research Fund, UK
  • 1986 Laboratory Head, Ludwig Institute for Cancer Research, UK
  • 1990 Principal Investigator at the Imperial Cancer Research Fund, UK (in 2002 the Imperial Cancer Research Fund became Cancer Research UK)
  • 2006 Head of the Division of Cancer Studies King's College London, UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK