Elsevier

Cellular Signalling

Volume 13, Issue 11, November 2001, Pages 777-785
Cellular Signalling

Review article
Regulation of MAP kinase activity by peptide receptor signalling pathway: Paradigms of multiplicity

https://doi.org/10.1016/S0898-6568(01)00192-9Get rights and content

Abstract

G protein-coupled receptors (GPCRs) can stimulate the mitogen-activated protein kinase (MAPK) cascade and thereby induce cellular proliferation like receptor tyrosine kinases (RTKs). Work over the past 5 years has established several models which reduce the links of Gi-, Gq-, and Gs-coupled receptors to MAPK on few principle pathways. They include (i) Ras-dependent activation of MAPK via transactivation of RTKs such as the epidermal growth factor receptor (EGFR) , (ii) Ras-independent MAPK activation via protein kinase C (PKC) that converges with the RTK signalling at the level of Raf, and (iii) activation as well as inactivation of MAPK via the cAMP/protein kinase A (PKA) pathway in dependency on the type of Raf. Most of these generalizing hypotheses are founded on experimental data obtained from expression studies and using a limited set of individual receptors. This review will compare these models with pathways to MAPK found for a great variety of peptide hormone and neuropeptide receptor subtypes in various cells. It becomes evident that under endogenous conditions, the transactivation pathway is less dominant as postulated, whereas pathways involving isoforms of PKC and, especially, phosphoinositide 3-kinase (PI-3K) appear to play a more important role as assumed so far. Highly cell-specific and unusual connections of signalling proteins towards MAPK, in particular tumour cells, might provide points of attacks for new therapeutic concepts.

Introduction

G protein-coupled receptors (GPCRs) mediate the signal transduction of a great diversity of extracellular signals including biogenic amines, eicosanoids, lipid moieties (e.g., lysophosphatidic acid), peptide and glycoprotein hormones, neuropeptides, proteases (e.g., thrombin) or neurotransmitters (e.g., glutamate or GABA) [1]. The important roles of these receptors in the short-term regulation of metabolism, secretion or contractility have been extensively studied. In the last years, it became evident that GPCRs, which are also expressed in proliferating cells, may elicit mitogenic responses by stimulating mitogen-activated protein kinase (MAPK) cascades [2], [3], [4]. The MAPK family consists of three subfamilies with multiple members: the extracellular-regulated kinases (ERKs), the Jun amino-terminal kinases/stress-activated kinases (JNKs/SAPKs), and the p38 MAPKs. Each MAPK is a member of a three-protein kinase cascade and subsequently activated by a MAPK kinase kinase (MKKK) and a MAPK kinase (MKK), which are organized in a MAPK module [5]. The best studied final target of GPCRs is the ERK 1/2 subfamily (also designated as p44 and p42 MAPK), which is classically associated with receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR). In the literature, frequently the term “MAPK” is used as a synonym for ERK 1/2. Sometimes, that will also be done in this article, which is referring to the ERK cascade only. Once activated, ERKs can phosphorylate and thereby activate transcription factors (e.g., Elk-1 or c-Myk), their own upstream regulators (e.g., EGFR or the Ras exchange factor Sos) or regulatory enzymes such as phospholipase A2. The downstream targets of ERKs then regulate cellular responses including proliferation and differentiation.

Almost all of the hitherto existing models describing pathways, which might link GPCRs to ERKs, are founded upon experimental data obtained from expression studies. The preferred experimental strategy is the transient coexpression of an epitope-tagged MAPK, together with a GPCR of interest in an easily transfectable cell line such as COS-7 cells, HEK 293 cells or Rat-1 cells. Alternatively, receptors endogenously expressed in these cell lines are used to investigate the activation of overexpressed epitope-tagged MAPK. With respect to their selective G protein coupling, several GPCRs have been mainly used in these studies, e.g., m1 and m2 muscarinic receptors [6], [7], [8], α1- and α2-adrenergic receptors [9], bombesin receptors [8] or bradykinin B2 receptors [10]. The mostly used endogenous receptors are lysophosphatidic acid (LPA) receptors, endothelin-1 receptors, thrombin receptors [8], [11] and, especially, β-adrenergic receptors [12], [13], [14], [15], [16], [17].

Several principal approaches were employed to identify the signalling molecules which may be involved in the biochemical routes from a GPCR to MAPK, for example:

  • ⋅ use of Pertussis toxin (PTX) and coexpression of specific Gβγ scavengers to decide whether Gα or Gβγ subunits of Gi or Gq family G proteins are involved;

  • ⋅ use of various specific inhibitors to identify putatively involved signalling mediators;

  • ⋅ overexpression of putative key signalling molecules to enhance the GPCR-induced activation of MAPK or of constitutively active mutants to imitate the effect evoked by GPCR stimulation; and, finally,

  • ⋅ coexpression of dominant negative mutants of key signalling molecules to confirm the involvement of a signalling protein of interest.

In that way, at least three principle mitogenic pathways from GPCRs to ERKs have been hypothesized: the transactivation pathway, the protein kinase C (PKC) pathway and the cAMP/protein kinase A (PKA) pathway.

Section snippets

Principle mechanisms of MAPK activation by GPCRs

Activation of the MAPK (ERK) cascade by RTKs, such as the EGFR, is initiated by binding of EGF to the monomeric receptor leading to EGFR dimerization, activation of intrinsic tyrosine kinase activity and transphosphorylation of the dimerized EGFR monomers. Phosphorylated tyrosine residues are docking sites for the adaptor proteins Shc and Grb2 with SH2 (Src homology 2) domains. Grb2 may bind to EGFR with or without Shc. The complex of Grb2 and the associated Ras guanine nucleotide exchange

Pathways linking various Gq/11- and Gi-coupled peptide receptors to the MAPK cascade

The majority of peptide receptors mediate stimulation of cell growth. In most cases, activation of ERK 1/2 is essentially involved in this process. In each case, the involvement of MAPK has to be confirmed by the use of specific inhibitors, e.g., the MEK inhibitor, PD 98059, in both proliferation assays and MAPK assays [32].

Several peptide receptors stimulate the MAPK cascade dominantly via Gq/11 proteins, for example, the angiotensin II AT1 receptor, the bradykinin B2 receptor, the vasopressin

Mitogenic pathways of Gs-coupled peptide receptors

The cAMP/PKA effector system represents the main signalling pathway mediated via a Gs protein. Pituitary adenylate cyclase-activating polypeptides (PACAP-27 and -38) are members of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family and have been shown to possess mitogenic activity in various tumour cells. Indeed, VIP activates MAPK via the cAMP/PKA pathway, e.g., in PC-12 cells. The biochemical routes from PACAP receptors to MAPK reflect, in contrast, the cell-specific

Cell growth-inhibiting pathways of peptide receptors

Up to now, there are only few examples suggesting antiproliferative actions of peptides. Somatostatin (SST), especially, has been found to be not only an inhibitor of hormone secretion but also to initiate cytotoxic (apoptosis) and cytostatic (growth arrest) antiproliferative effects on various tumour cells [89], [90]. The activity of MAPK may be differently regulated by SST. The diverse biological effects of SST (SST-14 and of the longer form SST-28) are mediated through a family of five

Summary and outlook

We can conclude that GPCRs employ more multiple strategies for the regulation of cell growth than assumed so far. The pathway connecting a particular GPCR to the MAPK cascade is highly cell-specific and may depend on the receptor type, the type of G protein and probably the availability, the concentration and the cellular localization of several signalling proteins with key functions. At the receptor level, in different cells, a single receptor type may stimulate MAPK activity either via one

Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Deutsche Krebshilfe.

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