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Review

New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation

Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Alessandro Cannavo
Int. J. Mol. Sci. 2021, 22(12), 6489; https://doi.org/10.3390/ijms22126489
Received: 31 May 2021 / Revised: 14 June 2021 / Accepted: 15 June 2021 / Published: 17 June 2021
Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)-mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much is known of their contribution to different signaling pathways. The suggested direct interaction between a GPCR and a SFK could allow for a potential immediate allosteric regulation of SFKs by GPCRs and thereby unravel a novel mechanism of SFK signaling. This overview will help to identify new GPCR–SFK interactions, which could serve to explain biological functions or be used to modulate downstream effectors. View Full-Text
Keywords: G protein-coupled receptors; GPCR; SFK; Src kinases; G proteins; arrestin; allosteric regulation; biased signaling; non-receptor tyrosine kinases; SH3 domains; polyproline motifs; kinase activation; signaling G protein-coupled receptors; GPCR; SFK; Src kinases; G proteins; arrestin; allosteric regulation; biased signaling; non-receptor tyrosine kinases; SH3 domains; polyproline motifs; kinase activation; signaling
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MDPI and ACS Style

Berndt, S.; Liebscher, I. New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation. Int. J. Mol. Sci. 2021, 22, 6489. https://doi.org/10.3390/ijms22126489

AMA Style

Berndt S, Liebscher I. New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation. International Journal of Molecular Sciences. 2021; 22(12):6489. https://doi.org/10.3390/ijms22126489

Chicago/Turabian Style

Berndt, Sandra, and Ines Liebscher. 2021. "New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation" International Journal of Molecular Sciences 22, no. 12: 6489. https://doi.org/10.3390/ijms22126489

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