Proto-oncogene tyrosine-protein kinase Src

Lua error in Module:Infobox_gene at line 33: attempt to index field 'wikibase' (a nil value). Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src or simply c-Src , is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. This protein phosphorylates specific tyrosine residues in other proteins. An elevated level of activity of c-Src tyrosine kinase is suggested to be linked to cancer progression by promoting other signals.^[1] c-Src includes an SH2 domain, an SH3 domain, and a 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 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 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.^[2] It belongs to a family of non-receptor tyrosine kinases called Src family kinases.

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 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.^[3]

Discovery

In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely related to v-Src.^[4] The normal cellular gene was called c-src (cellular-src).^[5] 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.

Structure and function

There are 9 members part of the Src family kinases: c-Src , Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck.^[6] 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.^[7]^[8]^[9]^[10]

c-Src is made up of 6 functional regions: Src homology (SH) 4 domain (SH4 domain), unique region, SH3 domain, 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 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 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.^[11]^[12]^[13]

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 receptor (PDGFR) pathway and epidermal growth factor receptor (EGFR). When src is activated, it promotes survival, angiogenesis, proliferation and invasion pathways. It also regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion.^[14]^[15]

Src contains at least three flexible protein domains, which, in conjunction with myristoylation, can mediate attachment to membranes and determine subcellular localization.^[16]

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.^[17] 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.^[18]^[19]^[20] 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.^[21]^[22]

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.^[23]^[24]^[25]

Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2), also known as erbB2, is correlated with a worse prognosis for breast cancer.^[26]^[27] 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.^[28] 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.^[29] 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.^[30] One notable example is dasatinib which has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (PH+) acute lymphocytic leukemia (ALL).^[31] 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,^[32] bafetinib, AZD-530, XLl-999, KX01 and XL228.^[1]

Interactions

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

Survival

Angiogenesis

Proliferation

Motility

Additional images

Overview of signal transduction pathways involved in apoptosis.

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Top row: Beta-strand region Hydrogen bonded turn Helical region Overlapping vertical annotations not shown above: 117-117

List of protein features
site	2	2	lipid-binding
site	17	17	Phosphoserine
site	35	35	Phosphoserine
site	69	69	Phosphoserine
site	74	74	Phosphothreonine
site	75	75	Phosphoserine; by CDK5
region	87	93	Beta-strand region
region	88	143	SH3_Src
site	88	88	swapped dimer interface [polypeptide binding]
site	93	93	peptide ligand binding site [polypeptide binding]
region	99	102	Beta-strand region
region	110	114	Beta-strand region
region	117	117	Splicing variant
region	118	126	Beta-strand region
region	127	129	Hydrogen bonded turn
region	132	136	Beta-strand region
region	137	139	Helical region
region	140	142	Beta-strand region
region	146	148	Helical region
region	147	247	SH2_Src_Src
region	152	154	Beta-strand region
site	158	158	autoinhibitory site [polypeptide binding]
site	158	158	phosphotyrosine binding pocket [polypeptide binding]
region	158	165	Helical region
region	167	170	Beta-strand region
region	174	179	Beta-strand region
region	176	176	Variant
region	181	183	Beta-strand region
region	187	195	Beta-strand region
site	187	187	Phosphotyrosine (By similarity)
region	196	198	Hydrogen bonded turn
region	199	209	Beta-strand region
site	205	205	hydrophobic binding pocket [polypeptide binding]
region	211	213	Beta-strand region
region	215	218	Beta-strand region
region	221	225	Beta-strand region
region	226	233	Helical region
region	237	237	Variant
region	240	242	Beta-strand region
region	256	259	Beta-strand region
region	267	269	Helical region
region	270	519	Pkinase_Tyr
region	270	278	Beta-strand region
site	276	276	ATP binding site [chemical binding]
region	283	289	Beta-strand region
site	290	290	SH3/SH2 domain interface [polypeptide binding]
region	290	292	Hydrogen bonded turn
region	293	299	Beta-strand region
site	298	298	ATP
region	302	304	Hydrogen bonded turn
region	307	319	Helical region
region	328	332	Beta-strand region
region	334	336	Beta-strand region
region	338	341	Beta-strand region
region	349	353	Helical region
region	355	358	Helical region
region	363	382	Helical region
site	389	389	Proton acceptor
region	392	394	Helical region
region	395	397	Beta-strand region
region	399	401	Helical region
region	403	405	Beta-strand region
site	406	406	activation loop (A-loop)
region	410	413	Helical region
region	417	420	Helical region
site	419	419	Phosphotyrosine; by autocatalysis; alternate
site	419	419	Phosphotyrosine; by FAK2; alternate (By similarity)
region	423	426	Hydrogen bonded turn
region	429	431	Helical region
region	434	439	Helical region
site	439	439	Phosphotyrosine
region	444	459	Helical region
region	460	462	Hydrogen bonded turn
region	471	479	Helical region
region	492	501	Helical region
site	501	501	S-nitrosocysteine (By similarity)
region	506	508	Helical region
site	511	511	Phosphothreonine
region	512	520	Helical region
region	521	523	Hydrogen bonded turn
site	522	522	Phosphotyrosine
site	530	530	Phosphotyrosine; by CSK