Proto-oncogene tyrosine-protein kinase Src

Last updated
SRC
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SRC , ASV, SRC1, c-p60-Src, SRC proto-oncogene, non-receptor tyrosine kinase, THC6
External IDs OMIM: 190090; MGI: 98397; HomoloGene: 21120; GeneCards: SRC; OMA:SRC - orthologs
EC number 2.7.10.2
Orthologs
SpeciesHumanMouse
Entrez

6714

20779

Ensembl

ENSG00000197122

ENSMUSG00000027646

UniProt

P12931

P05480

RefSeq (mRNA)

NM_005417
NM_198291

NM_001025395
NM_009271

RefSeq (protein)

NP_005408
NP_938033

NP_001020566
NP_033297

Location (UCSC) Chr 20: 37.34 – 37.41 Mb Chr 2: 157.42 – 157.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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), is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src (viral Src) gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene. [5]

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.

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. [7]

Discovery

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]

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).

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:

Survival

Angiogenesis

Proliferation

Motility

Additional images

Overview of signal transduction pathways involved in apoptosis. Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis.
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Top row:   Beta-strand region

   Hydrogen bonded turn    Helical region

site22lipid-binding
site1717Phosphoserine
site3535Phosphoserine
site6969Phosphoserine
site7474Phosphothreonine
site7575Phosphoserine; by CDK5
region8793Beta-strand region
region88143SH3
site8888swapped dimer interface [polypeptide binding]
site9393peptide ligand binding site [polypeptide binding]
region99102Beta-strand region
region110114Beta-strand region
region117117Splicing variant
region118126Beta-strand region
region127129Hydrogen bonded turn
region132136Beta-strand region
region137139Helical region
region140142Beta-strand region
region146148Helical region
region147247SH2
region152154Beta-strand region
site158158autoinhibitory site [polypeptide binding]
site158158phosphotyrosine binding pocket [polypeptide binding]
region158165Helical region
region167170Beta-strand region
region174179Beta-strand region
region176176Variant
region181183Beta-strand region
region187195Beta-strand region
site187187Phosphotyrosine (By similarity)
region196198Hydrogen bonded turn
region199209Beta-strand region
site205205hydrophobic binding pocket [polypeptide binding]
region211213Beta-strand region
region215218Beta-strand region
region221225Beta-strand region
region226233Helical region
region237237Variant
region240242Beta-strand region
region256259Beta-strand region
region267269Helical region
region270519Tyrosine kinase
region270278Beta-strand region
site276276Active site (ATP binding)
region283289Beta-strand region
site290290SH3/SH2 domain interface [polypeptide binding]
region290292Hydrogen bonded turn
region293299Beta-strand region
site298298ATP
region302304Hydrogen bonded turn
region307319Helical region
region328332Beta-strand region
region334336Beta-strand region
region338341Beta-strand region
region349353Helical region
region355358Helical region
region363382Helical region
site389389Proton acceptor
region392394Helical region
region395397Beta-strand region
region399401Helical region
region403405Beta-strand region
site406406activation loop (A-loop)
region410413Helical region
region417420Helical region
site419419Phosphotyrosine; by autocatalysis; alternate
site419419Phosphotyrosine; by FAK2; alternate (By similarity)
region423426Hydrogen bonded turn
region429431Helical region
region434439Helical region
site439439Phosphotyrosine
region444459Helical region
region460462Hydrogen bonded turn
region471479Helical region
region492501Helical region
site501501S-nitrosocysteine (By similarity)
region506508Helical region
site511511Phosphothreonine
region512520Helical region
region521523Hydrogen bonded turn
site522522Phosphotyrosine
site530530Phosphotyrosine; by CSK

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000197122 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027646 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: SRC v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)".
  6. 1 2 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.
  7. ↑ "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'
  8. ↑ 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.
  9. ↑ 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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  12. ↑ 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. PMID   7510261.
  13. ↑ 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. PMID   7835707.
  14. ↑ 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. PMID   7733928.
  15. ↑ Arbesú M, Maffei M, Cordeiro TN, Teixeira JM, Pérez Y, Bernadó P, Roche S, Pons M (March 2017). "The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases". Structure. 25 (4): 630–640.e4. doi: 10.1016/j.str.2017.02.011 . PMID   28319009.
  16. ↑ Cooper JA, Gould KL, Cartwright CA, Hunter T (March 1986). "Tyr527 is phosphorylated in pp60c-src: implications for regulation". Science. 231 (4744): 1431–4. Bibcode:1986Sci...231.1431C. doi:10.1126/science.2420005. PMID   2420005.
  17. ↑ Okada M, Nakagawa H (December 1989). "A protein tyrosine kinase involved in regulation of pp60c-src function". J. Biol. Chem. 264 (35): 20886–93. doi: 10.1016/S0021-9258(19)30019-5 . PMID   2480346.
  18. ↑ 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. S2CID   4363527.
  19. ↑ Kaplan JM, Varmus HE, Bishop JM (March 1990). "The src protein contains multiple domains for specific attachment to membranes". Molecular and Cellular Biology. 10 (3): 1000–9. doi:10.1128/mcb.10.3.1000. PMC   360952 . PMID   1689455.
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  27. ↑ Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE (January 2002). "Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis". Cancer. 94 (2): 344–51. doi: 10.1002/cncr.10221 . PMID   11900220. S2CID   2103781.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ Biscardi JS, Belsches AP, Parsons SJ (April 1998). "Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells". Mol. Carcinog. 21 (4): 261–72. doi:10.1002/(SICI)1098-2744(199804)21:4<261::AID-MC5>3.0.CO;2-N. PMID   9585256. S2CID   24236532.
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