Receptor tyrosine kinase signaling mechanisms: Devolving TrkA responses with phosphoproteomics

Article · November 2012with7 Reads
DOI: 10.1016/j.jbior.2012.10.006 · Source: PubMed
Abstract
Receptor tyrosine kinases (RTKs) function through protein kinase entities located in the intracellular domain of each protomer. Following activation by ligand binding, they selectively form phosphotyrosine residues by autocatalytic modification. Some of these sites are involved in maintaining the active conformation of the kinase, while others become docking sites for various adaptor/effector/scaffold proteins, which, after complexing with the receptor, then initiate further responses through cascades of post-translational modifications and the generation of lipid second messengers. Although there is substantial overlap in the pathways and activities stimulated by this superfamily, the molecular features of the endodomains of the sub-families and the moieties that they interact with to perpetrate their signals are surprisingly distinct, which may play a significant role in the regulation and responses of the individual RTK types. Some use large scaffold proteins as the basis for most, if not all, of their signal-generating interactions, while others have numerous receptor endodomain phosphotyrosine sites that are quite overlapping in specificity. The members of the Trk family of receptors each have several tyrosine residues that are phosphorylated following stimulation, including those in the kinase activation loop, but there are only two established sites (Y490 and Y785 on TrkA) that are known to be directly involved in signal propagation. Taking advantage of this limited repertoire of docking sites, we have applied phosphoproteomic methods to dissect the signaling responses of both the native protein and derivatives that have had these two sites modified. Interestingly, a clear subset that was not dependent on either docking site was identified. A comparison with a similar set of data for EGFR indicates a considerable degree of similarity in the downstream signaling profile between these two RTKs.
    • "In addition, some ligands such as EGF are monomeric, and their binding to their receptor induces a conformational change that shifts the intra-molecular loop and exposes a binding domain in the receptor that results in its dimerisation environment [15]. In others, the dimerisation of the ligand is required to activate the receptor chain (i.e., the NGF–TrkA system environment [16]). In the absence of the ligand, the activation loop self-regulates activation of the receptor because its " closed " conformation inhibits catalytic activity (cis-inhibition). "
    [Show abstract] [Hide abstract] ABSTRACT: Bone cancers are characterised by the development of tumour cells in bone sites, associated with a dysregulation of their environment. In the last two decades, numerous therapeutic strategies have been developped to target the cancer cells or tumour niche. As the crosstalk between these two entities is thightly controlled by the release of polypeptide mediators activating signaling pathways through several receptor tyrosine kinases (RTKs), RTK inhibitors have been designed. These inhibitors have shown exciting clinical impacts, such as imatinib mesylate which has become a reference treatment for chronic myeloid leukaemia and gastrointestinal tumours. The present review gives an overview of the main molecular and functional characteristics of RTKs, and focuses on the clinical applications that are envisaged and already assessed for the treatment of bone sarcomas and bone metastases.
    Full-text · Article · Jan 2015
    • "Moreover, the distribution of tyrosine residues, a subset of which are phosphorylated in each case and generally provide docking sites for adaptor/ scaffold/effector moieties, are also significantly different. This provides, in turn, a number of distinct means for propagating the signal from that receptor (Bradshaw et al., 2013). In the light of this diversity, it is somewhat surprising that there is considerable uniformity in the downstream pathways that are activated by different RTK families. "
    [Show abstract] [Hide abstract] ABSTRACT: Nerve growth factor (NGF) and its precursor (proNGF) are primarily considered as regulators of neuronal function that induce their responses via the tyrosine kinase receptor TrkA and the pan-neurotrophin receptor p75NTR. It has been generally held that NGF exerts its effects primarily through TrkA, inducing a cascade of tyrosine kinase-initiated responses, while proNGF binds more strongly to p75NTR. When this latter entity interacts with a third receptor, sortilin, apoptotic responses are induced in contrast to the survival/differentiation associated with the other two. Recent studies have outlined portions of the downstream phosphoproteome of TrkA in the neuronal PC12 cells and have clarified the contribution of individual docking sites in the TrkA endodomain. The patterns observed showed a similarity with the profile induced by the epidermal growth factor receptor, which is extensively associated with oncogenesis. Indeed, as with other neurotrophic factors, the distribution of TrkA and p75NTR is not limited to neuronal tissue, thus providing an array of targets outside the nervous systems. One such source is breast cancer cells, in which NGF and proNGF stimulate breast cancer cell survival/growth and enhance cell invasion, respectively. This latter activity is exerted via TrkA (as opposed to p75NTR) in conjunction with sortilin. Another tissue overexpressing proNGF is prostate cancer and here the ability of cancer cells to induce neuritogenesis has been implicated in cancer progression. These studies show that the non-neuronal functions of proNGF/NGF are likely integrated with their neuronal activities and point to the clinical utility of these growth factors and their receptors as biomarkers and therapeutic targets for metastasis and cancer pain. Copyright © 2014. Published by Elsevier Ltd.
    Full-text · Article · Nov 2014
    • "The JM and C-terminal tail regions differ in size and tyrosine content among family members, and these differences generate and propagate different intracellular signals. The total number of tyrosine residues found in each intracellular region and the number known to be modified differ significantly between superfamily members, and the distribution of tyrosine residues is quite variable [2,3]. For example, the intracellular region of the epidermal growth factor receptor (EGFR), which is a member of the ErbB receptor family (originally named because of the homology to the erythroblastoma viral gene product, v-erbB), has 20 tyrosine residues, 12 of which are known to be phosphorylated, while the intracellular region of TrkA, a member of the neurotrophin (NT) receptor family, contains 11 tyrosine residues, six of which can be phosphorylated. "
    [Show abstract] [Hide abstract] ABSTRACT: Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights.
    Full-text · Article · Jun 2014
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