Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors

doi:10.1016/S1359-6101(01)00024-7

Cytokine & Growth Factor Reviews

Volume 13, Issue 1, February 2002, Pages 11-17

https://doi.org/10.1016/S1359-6101(01)00024-7 Get rights and content

Abstract

Ligands for G protein-coupled receptors (GPCR) are capable of activating mitogenic receptor tyrosine kinases, in addition to the mitogen-activated protein (MAP) kinase signaling pathway and classic G protein-dependent signaling pathways involving adenylyl cyclase and phospholipase. For example, receptors for epidermal growth factor (EGF), insulin-like growth-1 and platelet-derived growth factor and can be transactivated through G protein-coupled receptors. Neurotrophins, such as NGF, BDNF and NT-3 also utilize receptor tyrosine kinases, namely TrkA, TrkB and TrkC. Recently, it has been shown that activation of Trk receptor tyrosine kinases can also occur via a G protein-coupled receptor mechanism, without involvement of neurotrophins. Adenosine and adenosine agonists can activate Trk receptor phosphorylation specifically through the seven transmembrane spanning adenosine 2A (A_2A) receptor. Several features of Trk receptor transactivation are noteworthy and differ significantly from other transactivation events. Trk receptor transactivation is slower and results in a selective increase in activated Akt. Unlike the biological actions of other tyrosine kinase receptors, increased Trk receptor activity by adenosine resulted in increased cell survival. This article will discuss potential mechanisms by which adenosine can activate trophic responses through Trk tyrosine kinase receptors.

Introduction

Many examples of transactivation of mitogenic growth factor receptors in response to G protein-coupled receptor (GPCR) signaling have now been reported. In each case, increased dimerization and tyrosine phosphorylation of receptor tyrosine kinases occurs, followed by association of receptors with tyrosine phosphorylated adaptor proteins and Ras-dependent activation of MAP kinases [1], [2]. A variety of diverse ligands for GPCRs including isoproterenol, thrombin, lysophosphatidic acid (LPA), endothelin, thyrotropin-releasing hormone, carbachol and angiotensin II rapidly increase epidermal growth factor (EGF) receptor autophosphorylation. The occurrence of these events in different cell backgrounds such as vascular smooth muscle, fibroblastic, neuronal and non-neuronal cells [3], [4], [5], [6] suggests that this is a general mechanism of cross-talk between these two receptor systems.

Through GPCR signaling, it is well established that adenylyl cyclase and cAMP levels are regulated, as well as phospholipase C (PLC) and MAP kinase activities. Therefore, GPCR and receptor tyrosine kinases both can activate MAP kinase signaling. Furthermore, these interactions imply that growth factor receptors may be viewed as substrates of GPCRs. Several issues are raised by these observations. What are the cellular mechanisms that account for these events? Second, how is downstream signaling by GPCR and receptor tyrosine kinases differentially regulated. What are the biological functions for cross-talk between GPCR signaling and receptor tyrosine kinases? Finally, growth factor receptors are normally associated with enhanced cell proliferation, but what is the significance of receptor transactivation in postmitotic cells in the nervous system? This article will focus on transactivation events involving neurotrophin receptor tyrosine kinases, which provide a number of insights into these questions.

Section snippets

Neurotrophin receptor transactivation

Neurotrophins represent a unique family of proteins required for cell survival, differentiation and plasticity during development of the nervous system. NGF, brain derived neurotrophic factor, neurotrophin-3 (NT-3) and NT-4 are produced as precursor proteins which are cleaved to mature proteins of 118–120 amino acids that associate as non-covalent homodimers [7]. The actions of neurotrophins are dictated by two classes of cell surface receptors, the Trk receptor tyrosine kinase and the p75

Mechanism of transactivation

A simple explanation for the effects of adenosine is that adenosine interacts directly with Trk receptors to promote dimerization and autophosphorylation of Trk receptors. However, binding experiments indicate that adenosine does not compete with NGF for binding to the TrkA receptor. This is relevant because the Trk binding site for NGF are represented by the IgG domains, which are also responsible for regulating dimerization [18]. Furthermore, adenosine displays a very short half life, which

Functional consequences of transactivated Trk receptors

Phosphatidylinositol 3-kinase (PI3-kinase)/Akt is an important pathway that is directly influenced by many receptor tyrosine kinases. That GPCR ligands such as adenosine use this pathway through a receptor tyrosine kinase represents a new cross-talk mechanism. The activity of Akt is widely accepted as a signaling module for neuronal cell survival [20]. The time course of Akt activation was very similar to TrkA autophosphorylation induced by adenosine. Activated Akt was observed well after an

Discussion

These findings indicate that small molecules acting through GPCRs may be used to promote trophic activities mediated by receptor tyrosine kinases. Adenosine can activate the neurotrophin signaling system in the absence of neurotrophins. This is significant since neurotrophins provide signals to promote neuronal survival, synaptic efficacy and plasticity in the nervous system. Depending upon the circumstances, adenosine may be neuroprotective against injury initiated by ischemia, hypoxia or

Acknowledgements

FSL was supported by the DeWitt-Wallace Fund in the New York Community Trust and an American Psychiatric Association PMRTP Fellowship and MVC was supported by grants from the NIH.

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Mini-reviewDistinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors

Abstract

Introduction

Section snippets

Neurotrophin receptor transactivation

Mechanism of transactivation

Functional consequences of transactivated Trk receptors

Discussion

Acknowledgements

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Curr. Opin. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

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Trends Pharm. Sci.

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Mini-review
Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors