Role of c-Src in Carcinogenesis and Drug Resistance

Abstract

The aberrant transformation of normal cells into cancer cells, known as carcinogenesis, is a complex process involving numerous genetic and molecular alterations in response to innate and environmental stimuli. The Src family kinases (SFK) are key components of signaling pathways implicated in carcinogenesis, with c-Src and its oncogenic counterpart v-Src often playing a significant role. The discovery of c-Src represents a compelling narrative highlighting groundbreaking discoveries and valuable insights into the molecular mechanisms underlying carcinogenesis. Upon oncogenic activation, c-Src activates multiple downstream signaling pathways, including the PI3K-AKT pathway, the Ras-MAPK pathway, the JAK-STAT3 pathway, and the FAK/Paxillin pathway, which are important for cell proliferation, survival, migration, invasion, metastasis, and drug resistance. In this review, we delve into the discovery of c-Src and v-Src, the structure of c-Src, and the molecular mechanisms that activate c-Src. We also focus on the various signaling pathways that c-Src employs to promote oncogenesis and resistance to chemotherapy drugs as well as molecularly targeted agents.

Keywords: c-Src; carcinogenesis; drug resistance; signal transduction; v-Src.

Figure 1

The structure of the human c-Src. The human Src protein is an orderly arrangement of four SH domains with N and C terminals. The C-terminal is the tail and anchors a regulatory tyrosine—Tyr530. SH1 domain is the highly catalytic tyrosine kinase (TK) domain with Tyr419 for substrate phosphorylation, ATP/inhibitor binding pocket, and an αC-helix. SH2 and SH3 domains are the regulatory domains that can bind phosphorylated Tyr530 and polyproline helix, respectively. The SH4 domain is the disordered segment and myristoylation site for membrane association [24,25].

Figure 2

Mechanism of Activation of c-Src: The kinase activity of c-Src is tightly regulated by the phosphorylation and dephosphorylation of Tyr530 and Tyr519 and depends on whether the kinase is in a “closed” or an “open” conformation. In normal cells, the basal activity of c-Src is maintained via a negative regulation by Tyr530. Phosphorylation of Tyr530 by the C-terminal Src kinase (Csk) enables high-affinity binding of phospho-Tyr530 to the SH2 domain, leading to the more compact “closed” conformation (inactive form). The “closed” conformation is further stabilized through interactions between the SH3 domain and a proline-rich region present in the kinase domain. Stimuli such as growth factors and integrins cause dephosphorylation of Tyr530 via activation of phosphatases (PTB1B, SHP1/2) or inactivation of Csk and disrupt the interaction of the SH2 domain with phospho-Tyr530, leading to an open conformation and allow autophosphorylation of Tyr419 (active form). Loss of the negative-regulatory C-terminal region due to viral integration in v-Src makes it CA as an oncogene. Some driver oncogenes constitutively activate c-Src.

Figure 3

Diagrammatic representation of the β-strands of the SH3 domain of human c-Src with the amino acid numbering [54]. The sequence of each β strand is underlined.

Figure 4

Schematic diagram of Src intracellular signaling pathway and various cellular processes controlled by each pathway. Activation of RTK, integrin signaling, or viral integration activates c-Src. Activated c-Src activates downstream PI3K-AKT, STAT3, Ras-MAPK, and FAK pathways and regulates various cellular functions required for normal growth and development as well as carcinogenesis and drug resistance. The both-way arrow indicates that the components can be activated by each other [88,89,90,91,92].