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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:88807 |
| Date | 03 January 2024 |
| Creators | Berndt, Sandra, Liebscher, Ines |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1422-0067, 10.3390/ijms22126489 |
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