Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src (cellular Src; pronounced "sarc", as it is short for

sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...

), is a non-receptor tyrosine kinase protein that in humans is encoded by the ''SRC''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It belongs to a family of

Src family kinase Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src (gene), Src, YES1, Yes, FYN, Fyn, and FGR (gene), Fgr, forming the SrcA subfamily, Lck, HCK, Hck, Tyrosine-protein kinase BLK, Blk, and Lyn (Src fam ...

s and is similar to the

v-Src v-Src is a gene found in Rous sarcoma virus (RSV) that encodes a tyrosine kinase that causes a type of cancer in chickens. The src gene is oncogenic as it triggers uncontrolled growth in abnormal host cells. It was the first retroviral oncogen ...

(viral Src) gene of Rous sarcoma virus. It includes an

SH2 domain The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains bind to phosphorylated tyrosine residues on other proteins, ...

, an

SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of ph ...

and a

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

domain. Two

transcript variants Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

encoding the same protein have been found for this gene. c-Src

phosphorylate In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

s specific

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

residues in other

s. It plays a role in the regulation of embryonic development and cell growth. An elevated level of activity of c-Src is suggested to be linked to cancer progression by promoting other signals. Mutations in c-Src could be involved in the malignant progression of

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

. c-Src should not be confused with CSK (C-terminal Src kinase), an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that phosphorylates c-Src at its

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

and provides negative regulation of Src's enzymatic activity. c-Src was originally discovered by American scientists J. Michael Bishop and Harold E. Varmus, for which they were awarded the 1989

Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, acco ...

Discovery

In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens possess a gene that is structurally closely related to ''

''. 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 In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral rep ...

into an abnormally functioning oncogene within the Rous sarcoma virus. Once the oncogene is transfected back into a chicken, it can lead to cancer.

Structure

There are 9 members of the Src family kinases: c-Src,

Yes Yes or YES may refer to: * An affirmative particle in the English language; see yes and no Education * YES Prep Public Schools, Houston, Texas, US * Young Eisner Scholars, in Los Angeles, New York City, Chicago, and Appalachia, US * Young Ep ...

, 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 4 domain (SH4 domain), unique region,

, 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 flexible linker domain and thereby keeps the inactive unit tightly bound. The activation of c-Src causes the dephosphorylation of the tyrosine 527. This induces long-range

allostery In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or Receptor (biochemistry), receptor distinct from the active site, resulting in a conformational ...

via protein domain dynamics, causing the structure to be destabilized, resulting in the opening up of the SH3, SH2 and kinase domains and the autophosphorylation of the residue tyrosine 416. c-Src can be activated by many transmembrane proteins that include: adhesion receptors,

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...

s, G-protein coupled receptors and

cytokine receptor Cytokine receptors are receptors that bind to cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly be ...

s. Most studies have looked at the receptor tyrosine kinases and examples of these are

platelet derived growth factor receptor Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellul ...

(PDGFR) pathway and

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...

(EGFR). Src contains at least three flexible protein domains, which, in conjunction with myristoylation, can mediate attachment to membranes and determine subcellular localization.

Function

This proto-oncogene may play a role in the regulation of embryonic development and cell growth. When src is activated, it promotes survival,

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

, proliferation and invasion pathways. It also regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion, and regulates matrix metalloproteinase-9 activity after intracerebral hemorrhage.

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 cancer

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 advanced 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. 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 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.

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 dasatinib which has been approved for the treatment of

chronic myeloid leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumula ...

(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 bosutinib, bafetinib, Saracatinib(AZD-0530), XLl-999, KX01 and XL228. HSP90 inhibitor NVP-BEP800 has been described to affect stability of Src tyrosine kinase and growth of T-cell and B-cell acute lymphoblastic leukemias.

Interactions

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

Survival

PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

* Akt * IKK * NFkB * Caspase 9

Angiogenesis

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...

* p38 MAPK * VEGF * IL-8 *

Proliferation

* Shc *

Grb2 Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/ cell communication. In humans, the GRB2 protein is encoded by the ''GRB2'' gene. The protein encoded by this gene binds recepto ...

/SOS * Ras * Raf * MEK1 / MEK2 * Erk1/2

Motility

* FAK * p190Rho/GAP * Paxillin * p130CAS *

RhoA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...

* JNK * c-jun * MLCK *

Myosin Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...

Additional images

References

External links

* * * - interactive 3D model of the structure of SRC
Vega geneview

Src
Info with links in th
Cell Migration Gateway
* {{Portal bar, Biology, border=no Oncogenes Genes mutated in mice Tyrosine kinases