Beyond 'furballs' and 'dumpling soups' - towards a molecular architecture of signaling complexes and networks.
The molecular architectures of intracellular signaling networks are largely unknown. Understanding their design principles and mechanisms of processing information is essential to grasp the molecular basis of virtually all biological processes. This is particularly challenging for human pathologies like cancers, as essentially each tumor is a unique disease with vastly deranged signaling networks. However, even in normal cells we know almost nothing. A few 'signalosomes', like the COP9 and the TCR signaling complexes have been described, but detailed structural information on their architectures is largely lacking. Similarly, many growth factor receptors, for example EGF receptor, insulin receptor and c-Met, signal via huge protein complexes built on large platform proteins (Gab, Irs/Dok, p130Cas[BCAR1], Frs families etc.), which are structurally not well understood. Subsequent higher order processing events remain even more enigmatic. We discuss here methods that can be employed to study signaling architectures, and the importance of too often neglected features like macromolecular crowding, intrinsic disorder in proteins and the sophisticated cellular infrastructures, which need to be carefully considered in order to develop a more mature understanding of cellular signal processing.
Biological Systems Architecture Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford OX3 9DS, United Kingdom. marc.lewitzky@imm.ox.ac.uk
Marc
M
Lewitzky
Philip C
PC
Simister
Stephan M
SM
Feller
D000818:Animals; D019295:Computational Biology / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D025941:Protein Interaction Mapping / Q000379:methods; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D005656:Fungal Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D066246:ErbB Receptors; D011972:Receptor, Insulin