SRC

Detailed Information

The SRC gene is located on human chromosome 20q11.23 and consists of 17 exons, encoding a non-receptor tyrosine kinase with a molecular weight of approximately 60 kDa. The gene is highly conserved, and its human homolog shares a high degree of similarity with the v-src oncogene of the Rous sarcoma virus. The SRC protein consists of four main structural domains: an N-terminal myristoylation site (which mediates membrane localization), an SH3 domain (which recognizes proline-rich motifs), an SH2 domain (which binds to phosphorylated tyrosine sites), and a C-terminal kinase domain (which catalyzes substrate phosphorylation). At the C-terminus, there is a key phosphorylation site at Tyr530 (corresponding to Tyr527 in humans), and its phosphorylation status determines SRC's activity: when Tyr527 is phosphorylated, SRC adopts a closed, self-inhibitory conformation; when this site is dephosphorylated, SRC transitions to an open, active conformation. SRC is widely expressed in various cell types, particularly in lymphocytes, osteoblasts, and neurons. As a central molecule in cellular signaling networks, SRC regulates a variety of biological processes, including cell proliferation, differentiation, migration, adhesion, and survival. Its activity is finely regulated by various post-translational modifications, including phosphorylation, dephosphorylation, acetylation, and ubiquitination.

Multidimensional Signaling Network

SRC serves as a multifunctional signaling node by phosphorylating specific tyrosine residues on substrate proteins, integrating extracellular signals from cell surface receptors (such as receptor tyrosine kinases, integrins, and G-protein-coupled receptors), and initiating downstream signaling cascades. In the regulation of cell adhesion and migration, SRC is a major upstream activator of FAK (focal adhesion kinase), forming a SRC-FAK signaling axis that regulates the assembly and dissociation of focal adhesions. Activated SRC phosphorylates FAK at the Tyr397 site, which in turn recruits other signaling molecules (e.g., PI3K, Grb2), ultimately affecting cytoskeletal remodeling and cell motility. In terms of cell proliferation and survival, SRC promotes cell cycle progression (particularly the G1/S transition) and inhibits apoptosis by activating the RAS-MAPK and PI3K-AKT pathways. Studies have shown that SRC can directly phosphorylate receptor tyrosine kinases such as PDGFR and EGFR, enhancing downstream signaling output. Additionally, SRC is involved in regulating immune receptor signaling (such as TCR, BCR), ion channel functions (e.g., BK channels), and synaptic transmission. Notably, the functions of SRC often overlap with those of other SRC family kinases (e.g., Lyn, Fyn, Yes), adding complexity to studies of its specific functions.

Figure 1. Schematic of the canonical Integrin/Src/FAK signalling network. (Parkin A, et al., 2019)

Subcellular Localization and Dynamic Regulation

The subcellular localization of SRC is crucial for its function. Through myristoylation at the N-terminus, SRC is localized to the inner side of the cell membrane, particularly at focal adhesions and cell-cell junctions. This membrane localization allows SRC to rapidly respond to extracellular signals. SRC is also present in the nucleus, where it regulates the activity of transcription factors (such as STAT3) and participates in DNA repair processes. The activation of SRC is a dynamic process: when the cell is in a resting state, Tyr527 at the C-terminus is phosphorylated by CSK kinase, causing the SH2 domain to bind to the phosphorylated tyrosine and the SH3 domain to link with the SH2-kinase domain, resulting in a closed conformation. When the cell is stimulated by growth factors, extracellular matrix, or cell-cell contact, phosphatases (such as PTP1B, SHP2) are activated, leading to dephosphorylation of Tyr527, which opens the SRC conformation and exposes the kinase domain. Simultaneously, the Tyr416 site in the kinase domain undergoes autophosphorylation, further enhancing SRC's kinase activity. Additionally, SRC can be activated through interactions with other proteins, such as viral or oncogenic proteins. For instance, the T antigen in polyomavirus and the HPV E6 protein can both activate SRC.

Embryonic Development and Tissue Homeostasis

During embryonic development, SRC plays a role in regulating critical events such as neural tube closure, bone formation, and angiogenesis. Gene knockout studies have shown that Src-null mice can survive but display mild osteosclerosis (bone resorption defects). However, when other family members (such as Yes or Fyn) are also knocked out, embryonic lethality occurs, suggesting functional redundancy among SRC family members. In osteoblasts, SRC forms a complex with PYK2 (focal adhesion kinase 2) and phosphorylates CBL proteins, activating the PI3K signaling pathway and promoting osteoclast bone resorption. Additionally, SRC contributes to osteoblast energy metabolism by activating mitochondrial cytochrome C oxidase to promote energy production. In the nervous system, SRC is involved in regulating synaptic plasticity and neuronal migration, with the SRC1B isoform (produced by alternative splicing) playing a specific role in neurite extension. In tissue injury repair, SRC mediates the IL-6-YAP1-NOTCH signaling axis, contributing to inflammation-induced epithelial regeneration. These studies highlight the multifunctional role of SRC in maintaining tissue homeostasis.

Tumorigenesis and Metastasis

SRC is one of the earliest identified proto-oncogenes, and its overactivation is closely linked to the development of various cancers. In colorectal cancer, SRC activity is positively correlated with tumor progression, and its activation can promote tumor cell proliferation via transcription factors such as AP-1 and STAT3. In breast cancer, SRC cooperates with HER2 by enhancing phosphorylation of FAK and p130Cas, promoting tumor invasion. In pancreatic cancer, upregulated SRC expression is associated with tumor staging and metastasis. The oncogenic mechanisms of SRC mainly include promoting epithelial-mesenchymal transition (EMT) to enhance invasiveness, regulating tumor angiogenesis (via VEGFR signaling), influencing metabolic reprogramming (such as enhancing glycolysis), and promoting immune evasion (by modulating immune checkpoint molecules). Notably, SRC is often not the initial driver of tumorigenesis but acts as a "signal amplifier," cooperating with other oncogenic signals (such as EGFR, HER2, MET) to promote tumor progression and metastasis. In the tumor microenvironment, SRC also regulates the activation of tumor-associated fibroblasts (CAFs) and extracellular matrix remodeling, creating favorable conditions for metastasis.

Drug Resistance and Tumor Microenvironment

SRC plays an important role in tumor drug resistance and microenvironment remodeling. Studies have found that in EGFR inhibitor-resistant lung cancer cells, SRC interacts physically and functionally with EGFR, activating alternative survival pathways (such as PI3K/AKT). In HER2-positive breast cancer, increased SRC activity is associated with resistance to trastuzumab, and combination therapy with SRC inhibitors can restore drug sensitivity. Additionally, SRC regulates tumor cell interactions with the extracellular matrix by modulating discoidin domain receptor (DDR). DDR1, a collagen-activated receptor tyrosine kinase, is highly expressed in various cancers, and its overexpression is significantly associated with lymph node metastasis. Studies have shown that DDR1 promotes the extracellular matrix (ECM) to become highly organized, hindering immune cell infiltration into tumors. SRC phosphorylates the tyrosine residues of DDR2, promoting its autophosphorylation, thereby influencing the immune-suppressive properties of the tumor microenvironment. In preclinical models, DDR1 knockout promotes T-cell infiltration and suppresses tumor growth, suggesting that targeting the SRC-DDR axis may be a new strategy to overcome the immunosuppressive microenvironment.