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Review
. 2020 May 27;21(11):3818.
doi: 10.3390/ijms21113818.

Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling

Maria Carmela Annunziata  1 , Melania Parisi  1 , Gabriella Esposito  2 , Gabriella Fabbrocini  1 , Rosario Ammendola  2 , Fabio Cattaneo  2
Affiliations
Review

Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling

Maria Carmela Annunziata et al. Int J Mol Sci. .

Abstract

FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. Herein, we discuss on the selective phosphorylation of Serine/Threonine-protein kinase N2, Serine/Threonine-protein kinase PRP4 homolog, Serine/Threonine-protein kinase MARK2, Serine/Threonine-protein kinase PAK4, Serine/Threonine-protein kinase 10, Dual specificity mitogen-activated protein kinase kinase 2, and Protein phosphatase 1 regulatory subunit 14A, triggered by FPR2 stimulation. We also describe the putative FPR2-dependent signaling cascades upstream to these specific phospho-sites.

Keywords: FPR2; MAP2K2; MARK2; PAK4; PKN2; PPP1R14A.; PRP4; STK10; cell signaling; phospho-sites.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
FPR2 signaling induces Thr958 phosphorylation of PKN2. Two proposed mechanisms for PKN2 activation. (a) FPR2 stimulation induces Rho signaling allowing a conformational change in PKN2 and the phosphorylation in the activation loop by PDK1. FPR2 triggers Rho-dependent PI3K activation both in β-arrestin-dependent or -independent manner. PI3K activates mTORC2 which phosphorylates PKN2 at Thr958 residue. (b) Phospho-tyrosines of trans-phosphorylated EGFR provide docking sites for NCK binding and the SH3 domains of the adapter protein bind PKN2 and Rho. Rho induces a conformational change of PKN2 which is required for binding to PDK1 and the phosphorylation in the activation loop. EGFR-induced PI3K activity triggers PIP3 synthesis which is required for mTORC2 activation and Thr958 phosphorylation in the turn phosphate motif.
Figure 2
Figure 2
FPR2-mediated EGFR transactivation induces Tyr849 phosphorylation of PRP4. FPR2 signaling induces the phosphorylation of cytosolic regulatory subunits of NADPH oxidase and, in turn, ROS generation which bridge the signals from FPR2 to EGFR. Phospho-tyrosine residues of EGFR provide docking sites for recruitment and triggering of not yet identified kinases, which in turn phosphorylate PRP4 at Tyr849 residue.
Figure 3
Figure 3
FPR2 signaling triggers MARK2 phosphorylation. FPR2 stimulation triggers Ras/MAPK pathway. We hypothesize that Ser486 residue of MARK2 is phosphorylated by not yet identified kinases downstream to Ras cascade.
Figure 4
Figure 4
FPR2 signaling induces PI3K-mediated Ser181 phosphorylation of PAK4. Binding of WKYMVm to FPR2 induces NADPH oxidase-dependent c-Met transactivation. Phospho-tyrosine residues of c-Met trigger PI3K signaling that promote PAK4 phosphorylation.
Figure 5
Figure 5
Structure-based sequence alignment of activation segment regions. The similar activation segments of STK10 and PAK4 are shown.
Figure 6
Figure 6
FPR2-mediated Thr394 phosphorylation of MEK2. Binding of WKYMVm to FPR2 triggers both Gi proteins-induced Ras/MEKs/ERKs signaling and ROS-dependent TKRs transactivation. Phosphorylated tyrosines of TKRs elicit Ras/MAPK pathway. Thr394 phosphorylation of MAP2K2 might depend on both signaling cascades.
Figure 7
Figure 7
Phosphorylation of Ser16 and Ser26 of CPI-17 depends on PKC and ROCK pathway. FPR2 signaling induces PKC- and/or ROCK activation which mediate Ser16 and Ser26 phosphorylation of CPI-17. RhoA-ROCK cascade could be also activated by β-arrestin-induced signaling.
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