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Advancements in The Ongoing Puzzle to Understand c-SRC

by Bellbrook Labs / Tuesday, 21 February 2023 / Published in Emerging Targets, Innate Immunity
Ongoing Puzzle of c-SRC in Cancer Treatment

Nearly a half-century ago, sequences from the Rous Sarcoma Virus were used to identify the first proto-oncogene and the first of a family of non-receptor tyrosine kinases: c-SRC. Unlike its viral counterpart (v-SRC), c-SRC exists in both an active and inactive state. It is produced in almost every cell type, but expressed highest in the brain, osteoclasts, and platelets. Two non-canonical isoforms, created by alternative splicing between exons 3 and 4, are primarily produced in nerve cells. c-SRC’s activation during the G2/M transition is crucial for cellular differentiation, proliferation, and survival. It is also important for cell adhesion, morphology, and motility, especially impacting bone resorption.1 Currently, the c-SRC mechanism is well-known but not fully understood, impacting the ability to produce effective modulators.3

Structure & Function

From front to back, the 60 kDa protein consists of the following:

  • a myristoylated N-terminal region that facilitates membrane association (SH4),
  • a unique domain (UD) that dictates its functional specificity
  • a protein interaction domain that is required for the suppression of SRC kinase activity (SH3)
  • a protein interaction domain that binds phosphorylated tyrosine residues internally and on other proteins (SH2)
  • the tyrosine kinase domain (SH1)
  • the C-regulatory tail domain, containing the regulatory tyrosine moiety, Y527, that interacts with the SH2 domain to repress Src kinase activity.

Essentially, the SH4 and UD domains inform membrane localization, the SH3 and SH2 domains cooperate to determine substrate recognition and facilitate negative kinase regulation, SH1 is the catalytic kinase domain, and the regulatory tail represses SH1 through interaction with SH2/SH3 when Y527 is phosphorylated. Csk (C-terminal Src kinase) is the usual agent that phosphorylates Y527 to inactivate c-SRC. In contrast, c-SRC is generally activated via PTP1B or Shp1/2 dephosphorylation of Y527. Various ligands and substances can also influence both activation and kinase activity.2

Problematic c-SRC Signaling

c-SRC is an intermediary for signaling from a variety of receptors at the plasma membrane, such as EGFR, HER2, c-Met, PDGFR, IGFR, and FGFR. Aberrant signaling from these receptors, via mutation or amplification, contributes to the survival and spread of many cancers, along with their resistance to chemotherapy. c-SRC signaling affects cellular mobility through its influence on Integrin and E-Cadherin. This signaling upregulates AKT expression to increase survival and MAPK expression, increasing proliferation. STAT3-induced angiogenesis is also increased through the action of c-SRC. While it’s activity has become a target of cancer therapies, c-SRC itself is only very rarely mutated in untreated, malignant tumors.2

In the past decade, ATP competitive inhibitors have targeted the c-SRC kinase domain’s adenosine binding motif and adjacent hydrophobic pocket. Dasatinib and bosutinib are examples of such drugs. While these drugs have demonstrated success, particularly against hematological cancers, they are prone to generating resistance. Furthermore, the binding of these kinase inhibitors conformationally changes c-SRC to an “active” shape, allowing it to associate with focal adhesion kinase (FAK). When therapeutic dosage wanes, the inhibitors dissociate from these c-SRC-FAK complexes, allowing c-SRC to phosphorylate FAK, initiating FAK-Grb2-mediated ERK signaling and enhancing proliferation. Prolonged kinase inhibitor treatments even select for c-SRC mutants with diminished inhibitor affinity (mimicking low drug concentrations) that enhance c-SRC phosphorylation of FAK and drive cancer progression.3

Perhaps, current revelations about the regulatory influence of micro RNAs and ubiquitination on c-SRC, as well as novel allosteric inhibitors, will lead to more effective therapies to restrict oncogenic signaling.4

Study c-SRC’s Kinase Domain with the Transcreener ADP² Assay

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References

1. Roskoski, R. (2004) Src protein-tyrosine kinase structure and regulation. Biochemical and Biophysical Research Communications, 324 (4), 1155- Review. https://doi.org/10.1016/j.bbrc.2004.09.171.

2. Roskoski, R. (2015) Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacological Research, 94, 9-25. Review. http://dx.doi.org/10.1016/j.phrs.2015.01.003.

3. Higuchi, M. et al. (2021) Paradoxical activation of c-Src as a drug- resistance mechanism. Cell Reports, 34, 108876. https://doi.org/10.1016/j.celrep.2021.108876.

4. Simatou, A. et al. (2020) Historical retrospective of the SRC oncogene and new perspectives (Review). Molecular and Clinical Oncology, 13, 21. Review. https://doi.org/10.3892/mco.2020.2091.

Tagged under: c-SRC, Innate Immunity, Kinase, Oncogene, tyrosine kinase inhibitors

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