Abstract
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.
Highlights
Src family kinases (SFKs) are upregulated in malignancies, and their expression levels as well as specific activity are elevated in brain, breast, colon, lung, and pancreatic carcinomas [2,3,4,5,6,7,8,9]
Yang et al showed that the receptor phospho-tail allosterically regulates the different conformations within the polyproline motifs in arrestin-2, which subsequently allows for domain
By comparing the active and basal crystal structures of arrestin-3 (PDB 3P2D for basal and 5TV1 for active arrestin-3) [71,78], we found that in the basal structure of arrestin-3, R96 stabilizes the polyproline loop in a potential inactive conformation through electrostatic interactions with the backbone of the amid bond of
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Src family kinases (SFKs) are non-receptor protein-tyrosine kinases that regulate essential processes such as cell proliferation, differentiation, survival, migration, and metabolism [1]. The human SFKs consist of eight typical family members (Src, Fyn, Yes, Fgr, Hck, Blk, Lck, and Lyn) and three atypical family members (Brk, Frk, Srms) based on sequence similarity. A majority of SFKs are essential in immune response; whereas Fyn and Lck are activated immediately after T-cell receptor stimulation, expression of Fgr, Hck, Lyn is induced in stimulated mature monocytes and macrophages [15]. Approved drugs for cancer treatment targeting Src family kinases, such as Dasatinib, show a high level of toxicity [18] due to their unselective inhibition of SFKs in cancer and healthy cells. In-depth structural, functional, and mechanistic knowledge of each single SFK in combination with a detailed understanding of their expression regulation can be the basis for a more specific therapeutic approach with limited side effects
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