Proto-oncogene tyrosine-protein kinase Src

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src or simply c-Src , is a non-receptor is_associated_with::tyrosine kinase protein that in humans is encoded by the SRC is_associated_with::gene. This protein is_associated_with::phosphorylates specific tyrosine residues in other protein s. An elevated level of activity of c-Src tyrosine kinase is suggested to be linked to cancer progression by promoting other signals. c-Src includes an is_associated_with::SH2 domain, an is_associated_with::SH3 domain, and a is_associated_with::tyrosine kinase domain.

c-Src stands for "cellular Src kinase" and should not be confused with "C-terminal Src kinase" (CSK) which is an enzyme which phosphorylates c-Src at its is_associated_with::C-terminus and provides negative regulation of Src's enzymatic activity. c-Src is a widely studied member of non-receptor tyrosine kinases which are not associated with a cell-surface receptor.

Src (pronounced "sarc" as it is short for is_associated_with::sarcoma) is a is_associated_with::proto-oncogene encoding a is_associated_with::tyrosine kinase originally discovered by is_associated_with::J. Michael Bishop and is_associated_with::Harold E. Varmus, for which they were awarded the 1989 is_associated_with::Nobel Prize in Physiology or Medicine. It belongs to a family of is_associated_with::non-receptor tyrosine kinases called is_associated_with::Src family kinases.

This gene is similar to the is_associated_with::v-Src gene of is_associated_with::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 CSK. 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.

Discovery
In 1979, is_associated_with::J. Michael Bishop and is_associated_with::Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely related to is_associated_with::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 is_associated_with::Rous sarcoma virus. Once the oncogene is transfected back into a chicken, it can lead to cancer.

Structure and function
There are 9 members part of the Src family kinases: c-Src (this protein), 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 (is_associated_with::SH4 domain), unique region, is_associated_with::SH3 domain, is_associated_with::SH2 domain, catalytic domain and short regulatory tail. When Src is inactive, the phosphorylated tyrosine group at the 527 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 527 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 416.

c-Src can be activated by many transmembrane proteins that include: is_associated_with::adhesion receptors, is_associated_with::receptor tyrosine kinases, is_associated_with::G-protein coupled receptors and is_associated_with::cytokine receptors. Most studies have looked at the receptor tyrosine kinases and examples of these are is_associated_with::platelet derived growth factor receptor (PDGFR) pathway and is_associated_with::epidermal growth factor receptor (EGFR). When src is activated, it promotes survival, is_associated_with::angiogenesis, proliferation and invasion pathways. It also regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion.

Src contains at least three domains which, in conjunction with myristylation, are capable of mediating attachment to membranes and determining subcellular localization.

Role 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 is 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
The activity of c-Src has been best characterized in colon cancer. Researchers have shown that Src expression is 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
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. 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 erbB2, is correlated with a worse prognosis for breast cancer. Thus, c-Src plays a key role in the tumor progression of breast cancers.

Prostate
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.

As a drug target
A number of tyrosine kinase inhibitors that target c-Src tyrosine kinase (as well as related tyrosine kinases) have been developed for therapeutic use. One notable example is is_associated_with::dasatinib which has been approved for the treatment of is_associated_with::chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (PH+) acute lymphocytic leukemia (ALL). Dasatinib is also in 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 include is_associated_with::bosutinib, is_associated_with::bafetinib, AZD-530, XLl-999, KX01 and XL228.

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

Survival

 * is_associated_with::PI3K
 * is_associated_with::Akt
 * IKK
 * is_associated_with::NFkB
 * is_associated_with::Caspase 9

Angiogenesis

 * is_associated_with::STAT3
 * p38 MAPK
 * is_associated_with::VEGF
 * IL-8

Proliferation

 * Shc
 * is_associated_with::Grb2/SOS
 * Ras
 * Raf
 * MEK1 / is_associated_with::MEK2
 * Erk1/2

Motility

 * FAK
 * p190Rho/GAP
 * is_associated_with::Paxillin
 * p130CAS
 * is_associated_with::RhoA
 * is_associated_with::JNK
 * is_associated_with::c-jun
 * is_associated_with::MLCK
 * is_associated_with::Myosin