Receptor tyrosine kinase signaling mechanisms: Devolving TrkA responses with phosphoproteomics
Dept. Pharmaceutical Chemistry, University of California, San Francisco, CA, USA. Electronic address: .
Advances in biological regulation
11/2012; 53(1). DOI: 10.1016/j.jbior.2012.10.006
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.
Available from: Aude I Ségaliny
- "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 . In others, the dimerisation of the ligand is required to activate the receptor chain (i.e., the NGF–TrkA system environment ). "
[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.
Journal of Bone Oncology 01/2015; 5(1). DOI:10.1016/j.jbo.2015.01.001 · 1.21 Impact Factor
Available from: Jay Pundavela
- "bly in length and in function . 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 . In the main , RTKs stimulate three main pathways : the activation of ERKs via Ras , GTP binding proteins and several other kinases ; the activation of phospholipas"
[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.
Advances in Biological Regulation 11/2014; 58. DOI:10.1016/j.jbior.2014.11.003
Available from: Rosalba D'Alessandro
- "Here we have extended the study to TrkA autophosphorylation and to its two main intracellular cascades, the ERK and PI3K cascades. At the TrkA receptor the lack of p75 NTR was found to affect the NGF-induced phosphorylation primarily at one tyrosine, Y490, the initiation site of the PI3K cascade (Bradshaw et al., 2013; Kaplan and Miller, 2000). Consistently with this finding the P-(T202/Y204)ERK, the marker of the ERK cascade, reached levels analogous to those of the wtPC12, although with some delay. "
[Show abstract] [Hide abstract]
ABSTRACT: PC12-27, a PC12 clone characterized by high levels of the transcription repressor REST and by very low mTORC2 activity, had been shown to be unresponsive to NGF, possibly because of its lack of the specific TrkA receptor. The neurotrophin receptor repressed by high REST in PC12-27 cells, however, is shown now to be not TrkA, which is normal, but p75(NTR), whose expression is inhibited at the transcriptional level. When treated with NGF, the PC12-27 cells lacking p75(NTR) exhibited a defective TrkA autophosphorylation restricted, however, to the TrkA(Y490) site, and an impairment of the PI3K signaling cascade. This defect was sustained in part by a mTORC1-dependent feed-back inhibition that in wtPC12 cells appeared marginal. Transfection of p75(NTR) to a level and surface distribution analogous to wtPC12 did not modify various high REST-dependent properties of PC12-27 cells such as high β-catenin, low TSC2 and high proliferation rate. In contrast, the defective PI3K signaling cascade and its associated mTORC2 activity were largely rescued together with the NGF-induced neurite outgrowth response. These changes were not due to p75(NTR) alone but required its cooperation with TrkA. Our results demonstrate that, in PC12, high REST induces alterations of NGF signaling which, however, are indirect, dependent on the repression of p75(NTR); and that the well-known potentiation by p75(NTR) of the TrkA signaling does not concern all the effects induced by NGF but primarily the PI3K cascade and its associated mTORC2, a complex known to play an important role in neural cell differentiation.
Biology Open 08/2013; 2(8):855-66. DOI:10.1242/bio.20135116 · 2.42 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.