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

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.

Src Family Kinases: A Potential Therapeutic Target for Acute Kidney Injury

“…Src, Fyn and Yes are expressed in almost all cell types [ 21 ]. On the contrary, Blk, Fgr, Hck, Lck, and Lyn are mainly found in hematopoietic cells [ 15 , 22 ]. Srms was first found in mouse neural precursor cells [ 23 ] and is widely expressed in normal mammalian tissue samples [ 15 , 20 ].…”

“…The phosphorylation of Tyr527 at C-teminal inactivates Src kinase by inhibiting autophosphorylation of Tyr416 in the catalytic domain [ 11 ]. Tyr527 is phosphorylated by Csk (C-terminal Src kinase) or Chk (Csk homologous kinase) [ 11 , 22 ]. The interaction between phosphorylated Tyr527 and the SH2 domain is helpful in maintaining the inactive state of SFKs [ 15 , 31 ].…”

The Activity of Novel BCR-ABL Small-Molecule Degraders Containing Pyrimidine Rings and Their Role in Overcoming Drug Resistance

“…BCR-ABL kinase is closely related to SRCfamily kinases (SFK), which make up the largest nonreceptor tyrosine kinase family in the human body, including LYN, FYN, LCK, HCK, FGR, BLK, YRK, YES, and c-SRC [28][29][30][31][32][33]. ey play a very important role in regulating cell proliferation, differentiation, adhesion, and movement [34][35][36], and abnormal expression of SFK members is related to the occurrence of various tumors in the human body [37][38][39]. Both BCR-ABL and SFK can promote the development of leukemia.…”

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

“…SFK is associated with intracellular signaling cascade, 154 extracellular stimulation, and activation of various types of receptors including EGFR and VEGF receptors. These receptors translate stimuli into various intracellular signals by triggering SFK.…”