Proto-oncogene tyrosine-protein kinase Src

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This article is about the kinase c-Src, for the kinase that phosphorylates c-Src, see CSK.
SRC proto-oncogene, non-receptor tyrosine kinase
PBB Protein SRC image.jpg
PDB rendering based on 1a07.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SRC ; ASV; SRC1; c-SRC; p60-Src
External IDs OMIM190090 MGI98397 HomoloGene21120 ChEMBL: 267 GeneCards: SRC Gene
EC number 2.7.10.2
RNA expression pattern
PBB GE SRC 213324 at.png
PBB GE SRC 221284 s at.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6714 20779
Ensembl ENSG00000197122 ENSMUSG00000027646
UniProt P12931 P05480
RefSeq (mRNA) NM_005417 NM_001025395
RefSeq (protein) NP_005408 NP_001020566
Location (UCSC) Chr 20:
35.97 – 36.03 Mb
Chr 2:
157.42 – 157.47 Mb
PubMed search [1] [2]

Proto-oncogene tyrosine-protein kinase Src also known as proto-oncogene c-Src or simply c-Src is a non-receptor protein 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 should not be confused with "cellular Src kinase" or "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[edit]

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[edit]

There are 9 members part of the Src family kinases: c-Src (this protein), 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 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.[11][12][13][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.

Role in cancer[edit]

The activation of the c-Src pathway has been observed in about 50% of tumors from colon, liver, lung, breast and the pancreas.[14] 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[edit]

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.[15][16][17] 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.[18][19]

Breast[edit]

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.[20][21][22]

Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2), also known as erbB2, is correlated with a worse prognosis for breast cancer.[23][24] Thus, c-Src plays a key role in the tumor progression of breast cancers.

Prostate[edit]

Members of the Src family kinases Src, Lyn and Fgr are highly expressed in malignant prostate cells compared to normal prostate cells.[25] 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.[26] So the use of a tyrosine kinase inhibitor is a possible way of reducing the progression of prostate cancers.

As a drug target[edit]

A number of tyrosine kinase inhibitors that target c-Src tyrosine kinase (as well as related tyrosine kinases) have been developed for therapeutic use.[27] 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).[28] 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,[29] bafetinib, AZD-530, XLl-999, KX01 and XL228.[1]

Interactions[edit]

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

Survival[edit]

Angiogenesis[edit]

Proliferation[edit]

Motility[edit]

Additional images[edit]

Overview of signal transduction pathways involved in apoptosis.
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Top row:    Beta-strand region    Hydrogen bonded turn    Helical region

References[edit]

  1. ^ a b Wheeler DL, Iida M, Dunn EF (July 2009). "The role of Src in solid tumors". Oncologist 14 (7): 667–78. doi:10.1634/theoncologist.2009-0009. PMC 3303596. PMID 19581523. 
  2. ^ "The Nobel Prize in Physiology or Medicine 1989: J. Michael Bishop, Harold E. Varmus". Nobelprize.org. 1989-10-09. "for their discovery of 'the cellular origin of retroviral oncogenes'" 
  3. ^ "Entrez Gene: SRC v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)". 
  4. ^ Stehelin D, Fujita DJ, Padgett T, Varmus HE, Bishop JM. (1977). "Detection and enumeration of transformation-defective strains of avian sarcoma virus with molecular hybridization". Virology 76 (2): 675–84. doi:10.1016/0042-6822(77)90250-1. PMID 190771. 
  5. ^ Oppermann H, Levinson AD, Varmus HE, Levintow L, Bishop JM (April 1979). "Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src)". Proc. Natl. Acad. Sci. U.S.A. 76 (4): 1804–8. Bibcode:1979PNAS...76.1804O. doi:10.1073/pnas.76.4.1804. PMC 383480. PMID 221907. 
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  13. ^ a b Nada S, Okada M, MacAuley A, Cooper JA, Nakagawa H (May 1991). "Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src". Nature 351 (6321): 69–72. Bibcode:1991Natur.351...69N. doi:10.1038/351069a0. PMID 1709258. 
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  15. ^ Bolen JB, Rosen N, Israel MA (November 1985). "Increased pp60c-src tyrosyl kinase activity in human neuroblastomas is associated with amino-terminal tyrosine phosphorylation of the src gene product". Proc. Natl. Acad. Sci. U.S.A. 82 (21): 7275–9. Bibcode:1985PNAS...82.7275B. doi:10.1073/pnas.82.21.7275. PMC 390832. PMID 2414774. 
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  17. ^ Talamonti MS, Roh MS, Curley SA, Gallick GE (January 1993). "Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer". J. Clin. Invest. 91 (1): 53–60. doi:10.1172/JCI116200. PMC 329994. PMID 7678609. 
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  19. ^ Cartwright CA, Meisler AI, Eckhart W (January 1990). "Activation of the pp60c-src protein kinase is an early event in colonic carcinogenesis". Proc. Natl. Acad. Sci. U.S.A. 87 (2): 558–62. Bibcode:1990PNAS...87..558C. doi:10.1073/pnas.87.2.558. PMC 53304. PMID 2105487. 
  20. ^ Ottenhoff-Kalff AE, Rijksen G, van Beurden EA, Hennipman A, Michels AA, Staal GE (September 1992). "Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product". Cancer Res. 52 (17): 4773–8. PMID 1380891. 
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  25. ^ Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, Mirosevich J, Lee FY, Jove R (October 2005). "Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells". Cancer Res. 65 (20): 9185–9. doi:10.1158/0008-5472.CAN-05-1731. PMID 16230377. 
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External links[edit]