Boster Pathways-> Kinase Signaling

G-Protein-Coupled Receptors Signaling to MAPK/Erk Pathway

G protein-coupled receptors (GPCRs) are activated by a wide variety of external stimuli. Upon receptor activation, the G protein exchanges GDP for GTP, causing the dissociation of the GTP-bound α and β/γ subunits and triggering diverse signaling cascades.

Overview of The GPCR Signaling TO MAPK/Erk PATHWAY

G Protein Coupled Receptors (GPCRs) regulate a broad range of normal biological processes and are implicated in the pathophysiology of a variety of diseases when their downstream signaling activities are dysregulated. GPCR signaling activates several intracellular signaling pathways, including the cAMP/PKA pathway, the PKC pathway, the Ca2+/NFAT pathway, the PLC pathway, the PTK pathway, the PKC/MEK pathway, the MAPK pathway, the p38 MAP pathway, the PI3K pathway, the Rho pathway, the NF-B pathway, and the JAK/STAT pathway. GPCRs are involved in the regulation of a broad range of biological processes, including vision, olfaction, the autonomic nervous system, and behavior. GPCRs Are Capable Of Recognizing A Wide Variety Of Ligands And Stimuli, Including Peptide And Non-Peptide Hormones And Neurotransmitters, Chemokines, Prostanoids, And Proteinases, Biogenic Amines, Nucleosides, Lipids, Growth Factors, Odorant Molecules, And Light.

To develop drug screening assays, it is necessary to conduct a survey of target and related GPCR expression and function in the chosen cell-based model system, as well as expression of related GPCRs to assess both direct and potential off-target effects.

gpcr Signaling Pathway in Action

One of the major cellular effectors activated by GPCRs is extracellular signal-regulated kinade including ERK1(MAPK 2) and ERK2(MAPK 1) which shares 85% sequence identity and are expressed in a wide variety of tissues and cells.

ERK pathway is a core signaling pathways that regulates a wide variety of cellular processes e.g growth,apoptosis,differentiation,proliferation e.t.c. Many stimuli including cytokines,growth factors and GPCRs ligand activate this pathway.its activation by GPCRs can be mediated by the activation of Ras,Rap,Pkc,tyrosine kinases or via beta-arrestins.

Unphosphorylated ERK is anchored in the cytoplasm by multiple components and forms a core signaling complex consisting of Raf.MEK and ERK.some proteins referred as scaffold proteins like the KSR,beta-arrestin,sef and IQGAP1 also interact with the tethered 3-kinase Raf/MEK/ERK architecture.

This interaction with the scaffold protein ensure signaling intergrity increasing its efficiency and target ERK1/2 to specific subcellular locations. ERK activation is achieved through sequential phosphorylation of a 3-kinase signaling architecture. Phosphorylated ERK1/2 are then released from the 3 kinase complex and then phosphorylate about 200 cellular substrates.

Subcellular distribution of activated ERK is regulated by interaction with various proteins,this promotes ERK cytoplasmic and nuclear retention e.g MEK 1 is responsible for both cytoplasmic retention of ERK prior to its activation and nuclear export after its dephosphorylation.

ERK1/2 is further phosphorylated by casein kinase 2 and are able to bind to a nuclear anchor protein for nuclear translocation,where they can phosphorylate and activate various transcription factors.

Gs, defined by the α-subunit Gαs, transduces signals from Gs-coupled heptahelical receptors to adenylyl cyclase that converts ATP to cAMP and subsequently to cAMP-mediated activation of protein kinase A (PKA). cAMP as well as cAMP-activated PKA have been shown to play a major role in Gαs-mediated stimulation as well as inhibition of MAPK modules such as those of ERK1/2, ERK5 and p38MAPK . The initial evidence that Gαs is involved in the regulation of ERK1/2 signaling module consisting of a MAP3K–MAP2K–MAPK module defined by Raf, MEK1/2 and ERK1/2, respectively, came from studies focused on defining the oncogenic pathways regulated by the gsp oncogene that encodes the constitutively activated mutants of Gαs . Functional characterization of these activating mutations indicated that the ectopic expression of Gαs could stimulate ERK1/2 in different cell types .

Using mutant S49 lymphoma cell lines that lack Gαs or PKA, it was further established that Gαs and PKA are required to couple β2-AR signaling to ERK1/2 module . Analysis of such Gαs-mediated stimulation of ERK1/2 indicated that it was mediated by a pathway involving Rap-1 and its activation of B-Raf, one of the isoforms of Raf.