c-Src phosphorylates specific tyrosine residues in other tyrosine kinases. 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.[6] Mutations in c-Src could be involved in the malignant progression of colon cancer. c-Src should not be confused with CSK (C-terminal Src kinase), an enzyme that phosphorylates c-Src at its C-terminus and provides negative regulation of Src's enzymatic activity.
In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens possess a gene that is structurally closely related to v-Src.[8] The normal cellular gene was called c-src (cellular-src).[9] 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
There are 9 members of the Src family kinases: c-Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck.[10] 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.[11][12][13][14]
c-Src is made up of 6 functional regions: Src homology 4 domain (SH4 domain), unique region, SH3 domain, SH2 domain, catalytic domain and short regulatory tail.[15] 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.[16][17][18]
Src contains at least three flexible protein domains, which, in conjunction with myristoylation, can mediate attachment to membranes and determine subcellular localization.[19]
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, proliferation and invasion pathways. It also regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion,[20][21] and regulates matrix metalloproteinase-9 activity after intracerebral hemorrhage.[22]
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.[23] 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.[24][25][26] 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.[27][28]
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.[29][30][31]
Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2), also known as erbB2, is correlated with a worse prognosis for breast cancer.[32][33] 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.[34] 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.[35] 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.[36] 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).[37] 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,[38]bafetinib, Saracatinib(AZD-0530), XLl-999, KX01 and XL228.[6] 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. [39]
Interactions
Src (gene) has been shown to interact with the following signaling pathways:
^Cance WG, Craven RJ, Bergman M, Xu L, Alitalo K, Liu ET (December 1994). "Rak, a novel nuclear tyrosine kinase expressed in epithelial cells". Cell Growth Differ. 5 (12): 1347–55. PMID7696183.
^Lee J, Wang Z, Luoh SM, Wood WI, Scadden DT (January 1994). "Cloning of FRK, a novel human intracellular SRC-like tyrosine kinase-encoding gene". Gene. 138 (1–2): 247–51. doi:10.1016/0378-1119(94)90817-6. PMID7510261.
^Oberg-Welsh C, Welsh M (January 1995). "Cloning of BSK, a murine FRK homologue with a specific pattern of tissue distribution". Gene. 152 (2): 239–42. doi:10.1016/0378-1119(94)00718-8. PMID7835707.
^Thuveson M, Albrecht D, Zürcher G, Andres AC, Ziemiecki A (April 1995). "iyk, a novel intracellular protein tyrosine kinase differentially expressed in the mouse mammary gland and intestine". Biochem. Biophys. Res. Commun. 209 (2): 582–9. doi:10.1006/bbrc.1995.1540. PMID7733928.
^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. PMID1709258. S2CID4363527.
^Dehm SM, Bonham K (April 2004). "SRC gene expression in human cancer: the role of transcriptional activation". Biochem. Cell Biol. 82 (2): 263–74. doi:10.1139/o03-077. PMID15060621.
^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. PMID1380891.
^Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (January 1987). "Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene". Science. 235 (4785): 177–82. Bibcode:1987Sci...235..177S. doi:10.1126/science.3798106. PMID3798106.
^Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (May 1989). "Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer". Science. 244 (4905): 707–12. Bibcode:1989Sci...244..707S. doi:10.1126/science.2470152. PMID2470152.
^Chang YM, Bai L, Yang I (2002). "Survey of Src activity and Src-related growth and migration in prostate cancer lines". Proc Am Assoc Cancer Res. 62: 2505a.
^Musumeci F, Schenone S, Brullo C, Botta M (April 2012). "An update on dual Src/Abl inhibitors". Future Med Chem. 4 (6): 799–822. doi:10.4155/fmc.12.29. PMID22530642.
