Signal Transduction

Receptor Kinases & Phosphatases

Receptors on the cell surface respond to changes in the cell’s environment, directing the cell to grow, proliferate, move, survive, differentiate (acquire specialized structures and/or functions), or undergo ‘apoptosis’ (programmed cell death) by activating specific signal transduction pathways. Carcinogenesis often begins with receptors being aberrantly activated, causing the cell to continuously grow and proliferate, and ignore signals to undergo apoptosis. This deregulated cell growth results in tumors.

Introduction

Cells can respond to their environment when a ‘ligand’, for example, a hormone, growth factor or cytokine, binds to a specific receptor. Ligand binding to the receptor results in ‘dimerization’ (physically pairing with another receptor), and the addition of a phosphate group to tyrosine, or serine and threonine amino acids (phosphorylation) in the sequences of protein mediators of signal transduction that are ‘downstream’ of the receptor, and/or in the intracellular domain of the receptor itself (autophosphorylation). Receptors that phosphorylate tyrosine amino acids are known as receptor tyrosine kinases (RTK), whilst receptors that phosphorylate serines and threonines are known as serine/threonine kinases. The phosphorylation activates the downstream signaling proteins, which activate others, and so on. In many cases the final target(s) of the ‘signal’ are the so-called ‘transcription factors’ in the nucleus. It is these transcription factors that cause certain genes to be ‘expressed’; transcribed into RNA that is then translated into proteins. The newly expressed proteins then carry out the steps necessary for the cell to respond to its environment, as directed by the receptor.

One of the first steps during carcinogenesis is the hijacking of the regulatory signals tha govern normal cell processes such as growth, proliferation, survival, and apoptosis. This is frequently achieved by the inappropriate activation of a receptor, either by genetic alterations that cause constitutive activation, or receptor ‘over-expression’, i.e. many more copies than usual of the receptor are present on the cell surface. Thus the signal transduction is continuous, or greatly amplified, respectively, causing the controls for normal cell processes to be over-ridden, and the cell to be able to grow and proliferate indefinitely.

LICR scientists have pioneered the studies of several receptors, and are now applying the knowledge gained from decades of investigation to develop cancer therapies and/or optimize existing therapies.

  • EGFR – the epidermal growth factor receptor (EGFR) is important in cell processes such as growth, differentiation, proliferation, survival, apoptosis, and migration. Overexpression of EGFR has been found in many different cancers, and as such, is being investigated as a potential target in the LICR’s Clinical Trials Program.
  • PDGFR – the platelet-derived growth factor receptor (PDGFR) plays a role in stimulating cell growth and migration, particularly the growth of stroma cells that form the framework around the body’s organs.
  • VEGFR – members of the vascular endothelial growth factor receptor (VEGFR) family are particularly important in the processes of angiogenesis, the formation of new blood vessels, and lymphangiogenesis, the formation of new lymph vessels, which are important for tumor growth (see also Angiogenesis Program).
  • TGF-β Program – the transforming growth factor-β receptor (TGFβR) is usually an inhibitor of cell growth, but during cancer development, tumor cells become resistant or respond aberrantly to TGFβR signals. TGFβR signaling is also important for angiogenesis (see also Angiogenesis Program).
  • RYK – an ‘orphan’ receptor, for which ligands have not yet been identified, but which appears to interact with Eph receptors, are thought to be involved in cell migration, particularly during embryogenesis.