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Starting a Molecular Systems View of Endocytosis ANRV356-CB24-20 ARI 3 September 2008 19:11 ANNUAL Protein Kinases: Starting REVIEWS Further Click here for quick links to Annual Reviews content online, a Molecular Systems View including: • Other articles in this volume of Endocytosis • Top cited articles • Top downloaded articles • Our comprehensive search Prisca Liberali, Pauli Ram¨ o,¨ and Lucas Pelkmans Institute of Molecular Systems Biology, ETH Zurich, CH-8093 Zurich, Switzerland; email: [email protected] Annu. Rev. Cell Dev. Biol. 2008. 24:501–23 Key Words First published online as a Review in Advance on membrane trafficking, phosphorylation, signal transduction, July 3, 2008 complexity, nonlinear systems, genetical physics The Annual Review of Cell and Developmental Biology is online at cellbio.annualreviews.org Abstract This article’s doi: The field of endocytosis is in strong need of formal biophysical model- 10.1146/annurev.cellbio.041008.145637 ing and mathematical analysis. At the same time, endocytosis must be Copyright c 2008 by Annual Reviews. much better integrated into cellular physiology to understand the for- by Universitat Zurich- Hauptbibliothek Irchel on 04/05/13. For personal use only. All rights reserved mer’s complex behavior in such a wide range of phenotypic variations. Annu. Rev. Cell Dev. Biol. 2008.24:501-523. Downloaded from www.annualreviews.org 1081-0706/08/1110-0501$20.00 Furthermore, the concept that endocytosis provides the space-time for signal transduction can now be experimentally addressed. In this review, we discuss these principles and argue for a systematic and top-down ap- proach to study the endocytic membrane system. We provide a summary of published observations on protein kinases regulating endocytic ma- chinery components and discuss global unbiased approaches to further map out kinase regulatory networks. In particular, protein phosphoryla- tion is at the heart of controlling the physical properties of endocytosis and of integrating these physical properties into the signal transduction networks of the cell to allow a fine-tuned response to the continuously varying physiological conditions of a cell. 501 ANRV356-CB24-20 ARI 3 September 2008 19:11 Thompson 2006, Miaczynska & Zerial 2002, Contents Soldati & Schliwa 2006). Although the gen- eral principle of endocytosis is always the COMPLEXITY IN same, there is not one particular series of THE ENDOCYTIC molecular events that always applies. Recent MEMBRANE SYSTEM ........... 502 progress in the field of endocytosis is rapidly WHY IS THE ENDOCYTIC dismissing our textbook view. Not only is the MEMBRANE SYSTEM contribution of clathrin-dependent processes IN HUMAN CELLS compared with alternative endocytic routes de- SO COMPLEX? .................. 503 bated in numerous instances, but also the def- ENDOCYTOSIS: SPACE-TIME inition of clathrin-mediated endocytosis finds FOR SIGNAL itself on loose ground. The canonical clathrin- TRANSDUCTION ............... 505 mediated route now appears to have differ- PROTEIN KINASES REGULATING ent variants, which can make use of different ENDOCYTIC MACHINERY ..... 506 adaptors, different GTPases, and different traf- MODULES OF ENDOCYTIC ficking itineraries and can bypass the canoni- MACHINERY COMPONENTS cal early endosome (Lakadamyali et al. 2006, REGULATED BY Schmid & McMahon 2007). Also, recent work PHOSPHORYLATION ........... 511 on entry has shown that Adaptor Module ................... 512 Listeria monocytogenes clathrin can assemble into very large lattices Coat Module ...................... 512 that appear to support a form of phagocyto- Membrane-Shaping Module ........ 513 sis (Veiga & Cossart 2005). The more these Membrane Fission Module ......... 513 differences are studied, the more it becomes Actin Cytoskeleton Module ........ 515 clear that only clathrin is the common factor. Molecular-Motors Module ......... 516 Thus, although the term clathrin-dependent Membrane Docking Module ....... 516 endocytosis incorporates all these variants, it Membrane Fusion Module ......... 516 is hard to maintain the view that from a GTPase Cascade Module........... 516 functional perspective, these are all just one UNBIASED GLOBAL route. Similar controversies are programmed APPROACHES TO LINK to arise (if they have not already arisen) for ENDOCYTOSIS TO KINASE terms such as caveolae-mediated, fluid phase, or REGULATORY NETWORKS macropinocytosis (Lajoie & Nabi 2007, Mayor OF THE CELL ................... 517 & Pagano 2007). CONCLUSIONS AND The above-discussed impasse in the field of OUTLOOK ...................... 518 endocytosis is probably exemplary for several by Universitat Zurich- Hauptbibliothek Irchel on 04/05/13. For personal use only. impasses in molecular cell biology and should Annu. Rev. Cell Dev. Biol. 2008.24:501-523. Downloaded from www.annualreviews.org be blamed on our highly reductionist, molecu- lar, and deterministic approach to these prob- COMPLEXITY IN lems in a time when global and unbiased com- THE ENDOCYTIC parisons were not possible. All pathways in cell MEMBRANE SYSTEM biology will likely have to be redefined with un- The endocytic membrane system in mam- biased global and quantitative methods, reveal- malian cells is complex. The basic steps of mem- ing a standardized set of rules and definitions brane trafficking—cargo recruitment, vesicle (Kirschner 2005, Mogilner et al. 2006). In one formation, vesicle transport, vesicle docking, sense, we can compare this transition in biology and vesicle fusion—are a concerted series with that in chemistry approximately 150 years of events that involves many different pro- ago. At that time, alchemy (reluctantly) gave teins and lipids (Gruenberg 2001, McNiven & way to modern-day chemistry, founded on a 502 Liberali · R¨am¨o · Pelkmans ANRV356-CB24-20 ARI 3 September 2008 19:11 standardized set of rules and definitions dis- covered by Antoine Lavoisier, who started to DEFINITION OF COMPLEXITY meticulously weigh metals, gases, liquids, and all kinds of materials and chemicals without any A complex system is a system composed of interconnected parts a priori hypothesis of a periodic table (Lavoisier that as a whole displays properties not obvious from the individ- 1789). He might have believed in finding some- ual parts (Adami 2002, Ricard 2003). This makes every biological thing fundamental in the data, but there was system with some nonlinear properties (like a simple feedback no scientific foundation for that belief. This loop) complex. The field of complex systems theory adds that a probably seems boring to many modern-day system is complex when there are difficulties with its bottom-up scientists, but from the accurate study of a com- formal modeling and simulation. For systems biology, this means prehensive set of measurements, a systematic that the system cannot be accurately modeled by a set of deter- pattern was discovered. ministic equations (for instance, differential equations) (Huang & We will thus have to go through a phase of Wikswo 2006). It is often argued that this is because the system’s painstakingly measuring, in an unbiased man- components, their concentrations, and their ways of interaction ner, as many relevant properties of cellular sys- are not (yet) known. But there are fundamental nondeterministic tems as possible. Essential for this phase will be properties (such as stochastic behavior) that, when amplified or methods to quantify large populations of sin- dampened in nonlinear ways, make nonstatistical models inap- gle molecules and single particles; to quantify propriate. One may regard this basic property as the uncertainty large populations of individual cells (eventu- principle in biology. The biological uncertainty principle seems ally within tissues); and to quantify functional particularly relevant for dynamic systems that consist of many roles of whole genomes (of which the protein- different components and interactions that span several orders of encoding part is just a fraction), of whole pro- magnitude on the space-time scale. It is likely that a crucial system teomes (including the enormous complexity of such as endocytosis has many built-in mechanisms to deal with posttranslational modifications), and of the in- this uncertainty, but this remains to be experimentally addressed. teractions between them. One can predict that when genome-wide functional analysis of en- docytosis in mammalian cells becomes more in human cells. This phase may be expensive, accurate and quantitative and can incorpo- take a long time, and require a large and com- rate quantitative properties of all vesicles in plex infrastructure. However, this concept can a cell and all cells in a cell population, we be applied to smaller sets of genes, proteins, and might be astonished by the number of differ- physical properties (Pelkmans et al. 2005). The ences between the internalization of two ligands iterative process of thinking about the principal that both use clathrin-dependent endocytosis. components of the endocytic membrane system Nevertheless, when this is done for a dozen on which to focus first to reveal the data and to of such ligands, the data might reveal certain use those data to think about how to expand the by Universitat Zurich- Hauptbibliothek Irchel on 04/05/13. For personal use only. patterns, some of which we have no notion of initial focus will reveal sets of rules and defini- Annu. Rev. Cell Dev. Biol. 2008.24:501-523. Downloaded from www.annualreviews.org today. We will find functional modules of cel- tions better and quicker and will optimize them lular components, which
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