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Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.

Src (pronounced "sarc" as it is short for sarcoma) is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they were awarded the 1989 Nobel Prize in Physiology or Medicine. It belongs to a family of non-receptor tyrosine kinases called Src family kinases. There are 9 members part of the Src family kinases: Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck. The expression of these Src family members are not the same throughout all tissues and cell types. Src, Fyn and Yes are expressed ubiquitously in all cell types while the others are generally found in hematopoietic cells. The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signaling has gone awry.

This gene is similar to the v-Src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-Src kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene.

v-Src
Francis Peyton Rous first proposed that viruses can cause cancer. He proved it in 1911 and was later awarded the Nobel prize in 1966. Chickens grow a tumor called a fibrosarcoma. Rous collected and ground up these sarcomas, and then centrifuged them to remove the solid material. Next, the remaining liquid mixture was injected into chicks. The chicks developed sarcomas. The causative agent in the liquid was a virus, this is now called the Rous sarcoma virus (RSV).

Further research done later on by others showed that RSV was a type of retrovirus. It was found that the v-Src gene in RSV is required for the formation of cancer.

A function for Src tyrosine kinases in normal cell growth was first demonstrated with the binding of family member p56lck to the cytoplasmic tail of the CD4 and CD8 co-receptors on T-cells. Src tyrosine kinases also transmit integrin-dependent signals central to cell movement and proliferation. Hallmarks of v-Src induced transformation are rounding of the cell and the formation of actin rich podosomes on the basal surface of the cell. These structures are correlated with increased invasiveness, a process thought to be essential for metastasis.

v-Src lacks the C-terminal inhibitory phosphorylation site (tyrosine-527), and is therefore constitutively active as opposed to normal Src (c-Src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-Src is therefore an instructive example of an oncogene whereas c-Src is a proto-oncogene.

The first sequence of v-Src was published in 1980 and the characterization of sites for tyrosine phosphorylation in the transforming protein of Rous sarcoma virus and its normal cellular homologue was published in 1981.

c-Src
In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely related to v-src. The normal cellular gene was called c-src (cellular-src). This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer. It is believed that at one point an ancestral virus mistakenly incorporated the c-Src gene of its cellular host. Eventually this normal gene mutated into an abnormally functioning oncogene within the Rous sarcoma virus. Once the oncogene is transfected back into a chicken, it can lead to cancer.

c-Src is made up of 6 functional regions: Src homology (SH) 4 domain, unique region, SH3 domain, SH2 domain, catalytic domain and short regulatory tail. When Src is inactive, the phosphorylated tyrosine group at the 530 position interacts with the SH2 domain which helps the SH3 domain interact with the linker domain and consequently keeps the inactive unit tightly bound. The activation of c-Src causes the dephosphorylation of the tyrosine 530 which causes the structure to be destabilized and then result in the opening up of the SH3, SH2 and the kinase domains and autophosphorylation of tyrosine 419 . c-Src can be activated by many transmembrane proteins that include: adhesion receptors, receptor tyrosine kinases, G-protein coupled receptors and cytokine receptors. Most studies have looked at the receptor tyrosine kinases and examples of these are platelet derived growth factor (PDGF) receptor pathway and epidermal growth factor receptor (EGFR). When Src is activated, it promotes survival, angiogenesis, proliferation and invasion pathways.

c-Src in cancer
The activation of the c-Src pathway has been observed in about 50% of tumors from colon, liver, lung, breast and the pancreas. Since the activation of c-Src leads to the promotion of survival, angiogenesis, proliferation and invasion pathways, the aberrant growth of tumors in cancers are observed. A common mechanism is that there are genetic mutations that result in the increased activity or the overexpression of the c-Src leading to the constant activation of the c-Src.

c-Src related cancers

 * Colorectal
 * Liver
 * Lung
 * Breast
 * Pancreas

Interactions
Src (gene) has been shown to interact with the following signaling pathways:

Survival Signal Transduction Pathways

 * PI3K
 * Akt
 * IKK
 * NFkB
 * Caspase 9

Angiogenesis Signal Transduction Pathways

 * STAT3
 * p38 MAPK
 * VEGF
 * IL-8

Proliferation Signal Transduction Pathways

 * Shc
 * Grb2/SOS
 * Ras
 * Raf
 * MEK1/2
 * Erk1/2

Motility Signal Transduction Pathways

 * FAK
 * p190Rho/GAP
 * Paxillin
 * p130CAS
 * RhoA
 * JNK
 * c-JUN
 * MLCK
 * Myosin

c-Src tyrosine kinase
c-Src tyrosine kinase, is a nonreceptor tyrosine kinase protein encoded by the SRC. It includes an SH2 domain, an SH3 domain, and a tyrosine kinase domain. This protein phosphorylates a carboxyl-terminus tyrosine residue on human Src, which acts as a negative regulatory site. An elevated level of activity of c-Src tyrosine kinase is suggested to be linked to cancer progression by promoting other signals.

Function
There are 9 members part of the Src family kinases: Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck. The expression of these Src family members are not the same throughout all tissues and cell types. Src, Fyn and Yes are expressed ubiquitously in all cell types while the others are generally found in hematopoietic cells. c-Src is made up of 6 functional regions: Src homology (SH) 4 domain, unique region, SH3 domain, SH2 domain, catalytic domain and short regulatory tail. When Src is inactive, the phosphorylated tyrosine group at the 530 position interacts with the SH2 domain which helps the SH3 domain interact with the linker domain and consequently keeps the inactive unit tightly bound. The activation of c-Src causes the dephosphorylation of the tyrosine 530 which causes the structure to be destabilized and then result in the opening up of the SH3, SH2 and the kinase domains and autophosphorylation of tyrosine 419 . c-Src can be activated by many transmembrane proteins that include: adhesion receptors, receptor tyrosine kinases, G-protein coupled receptors and cytokine receptors. Most studies have looked at the receptor tyrosine kinases and examples of these are platelet derived growth factor (PDGF) receptor pathway and epidermal growth factor receptor (EGFR). When src is activated, it promotes survival, angiogenesis, proliferation and invasion pathways.

c-Src in cancer
The activation of the c-Src pathway has been observed in about 50% of tumors from colon, liver, lung, breast and the pancreas. Since the activation of c-Src leads to the promotion of survival, angiogenesis, proliferation and invasion pathways, the aberrant growth of tumors in cancers are observed. A common mechanism is that there are genetic mutations that result in the increased activity or the overexpression of the c-Src leading to the constant activation of the c-Src.

Colon Cancer
The activity of c-Src has been best characterized in colon cancer. Researchers have shown that Src expression are 5 to 8 fold higher in premalignant polyps than normal mucosa. The elevated c-Src levels have also been shown to have a correlation with advances stages of the tumor, size of tumor, and metastatic potential of tumors.

Breast Cancer
EGFR activates c-Src while EGF also increases the activity of c-Src. In addition, overexpression of c-Src increases the response of EGFR-mediated processes. So both EGFR and c-Src enhance the effects of one another to Elevated expression levels of c-Src were found in human breast cancer tissues compared to normal tissues. Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2), also known as EGFR, is correlated with a worse prognosis for breast cancer. Thus, c-Src plays a key role in the tumor progression of breast cancers.

Prostate Cancer
Members of the Src family kinases Src, Lyn and Fgr are highly expressed in malignant prostate cells compared to normal prostate cells. When the primary prostate cells are treated with KRX-123, which is an inhibitor of Lyn, the cells in vitro were reduced in proliferation, migration and invasive potential. So the use of a tyrosine kinase inhibitor is a possible way of reducing the progression of prostate cancers.

c-Src targeting
In order to target the c-Src tyrosine kinase, the different tyrosine kinase inhibitors have been used. One of which is Dasatinib which is FDA approved for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (PH+) acute lymphocytic leukemia (ALL). Dasatinib is in phase I and II clinical trials for the use in non-Hodgkin’s lymphoma, metastatic breast cancer and prostate cancer. Other tyrosine kinase inhibitor drugs that are in clinical trials are Bosutinib, AZD-530, XLl-999, INNO-406, KX01 and XL228.