MAP Kinase Activation by Receptor Tyrosine Kinases: In Control of Cell Migration
A myriad of cellular processes instigated by growth factors are mediated by cell surface-associated receptor tyrosine kinases (RTKs). Subsequent downstream activation of signaling cascades, as well as their crosstalk, endows specificity in terms of the ph
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1. Introduction Animal cells constantly exchange information with their tissue environment by means of signaling molecules (e.g., growth factors; GFs) and structural components (e.g., extracellular matrix; ECM). These molecules harbor essential information, which enables orchestration of key cellular functions leading to proliferation, differentiation or migration. One important class of environmentsensing molecules are receptor tyrosine kinases (RTKs) (1). RTKs are type I transmembrane proteins with an extracellular ligandbinding domain, a kinase domain, and multiple tyrosine phosphorylation sites with regulatory functions. Upon ligand binding, receptors dimerize, thus activating their kinase domains and forming a signaling complex with auto- and trans-phosphorylation capabilities, thereby allowing recruitment of Src homology 2 (SH2) Rony Seger (ed.), MAP Kinase Signaling Protocols: Second Edition, Methods in Molecular Biology, vol. 661, DOI 10.1007/978-1-60761-795-2_7, © Springer Science+Business Media, LLC 2010
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and phosphotyrosine-binding (PTB) containing signaling adaptors (2). One of the most extensively studied subfamily of RTKs is the ErbB group, composed of four family members, each with its own binding partners and signaling capabilities (3, 4). The prototype of the ErbB family is the epidermal growth factor receptor (EGFR or ErbB-1). EGFR binds not only with EGF, but also with six more ligand growth factors. Upon ligand binding, EGFR is capable of recruiting effector molecules of a variety of signaling cascades, including the mitogen-activated protein kinase cascades (MAPK), phosphatidylinositol 3 kinase (PI3K), signal transducers and activators of transcription (STAT) and phospholipase Cg (PLCg) pathways (reviewed in (5)). The activation of these pathways defines the nature of the cellular response, as well as permits signal amplification. One striking feature of this configuration is the ability of a canonical linear pathway to generate several distinct cellular outcomes. A well-defined system exemplifying the ability of a linear cascade to generate multiple phenotypes is the proliferation vs. neurite outgrowth example, first exemplified using rat adrenal pheochromocytoma (PC-12) cells (6). In this system, proliferation can be induced by EGF or insulin, while neurite outgrowth is induced by the nerve growth factor (NGF), both utilizing the ERK1/2 cascade. Among other parameters, outcome specificity is encoded by the duration of ERK1/2 phosphorylation: transient activation leads to cell proliferation, whereas sustained activation results in neuronal differentiation (6). It was later shown that the topology of the MAPK network enables this dichotomy; only the transient mode of activation can induce negative feedback (7). It has long been realized that equally important in shaping the cellular outcome of GF stimulation is the transcriptional response elicited downstream to MAPK and other pathways (8). Recently it has been shown that the transcriptional activation of a module
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