Src (gene)
Encyclopedia
Proto-oncogene tyrosine-protein kinase Src is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that in humans is encoded by the SRC gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

.

Src ' onMouseout='HidePop("24657")' href="/topics/Sarcoma">sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...

) is a proto-oncogene encoding a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

 originally discovered by J. Michael Bishop
J. Michael Bishop
-External links:**...

 and Harold E. Varmus
Harold E. Varmus
Harold Elliot Varmus is an American Nobel Prize-winning scientist and the 14th and current Director of the National Cancer Institute, a post he was appointed to by President Barack Obama. He was a co-recipient Harold Elliot Varmus (born December 18, 1939) is an American Nobel Prize-winning...

, for which they won the 1989 Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

. It belongs to a family of non-receptor tyrosine kinase
Non-receptor tyrosine kinase
Non-receptor tyrosine kinases or non-specific protein-tyrosine kinases are enzymes that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Non-receptor tyrosine kinases are a subgroup of the larger class of tyrosine kinases...

s called Src family kinase
Src family kinase
Src family kinase is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily...

s. The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signalling has gone awry.

This gene is similar to the v-src gene of Rous sarcoma virus
Rous sarcoma virus
Rous sarcoma virus is a retrovirus and is the first oncovirus to have been described: it causes sarcoma in chickens.As with all retroviruses, it reverse transcribes its RNA genome into cDNA before integration into the host DNA.-History:...

. 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 c-SRC kinase. 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.

v-src

Francis Peyton Rous
Francis Peyton Rous
Peyton Rous born in Baltimore, Maryland in 1879 and received his B.A. and M.D. from Johns Hopkins University. He was involved in the discovery of the role of viruses in the transmission of certain types of cancer...

 first proposed that viruses can cause cancer. He proved it in 1911 and was later awarded the Nobel prize in 1966. Chickens grow a tumor called a fibrosarcoma. Rous ground up these sarcomas, centrifuged them to remove the solid material, and injected the remaining liquid into chicks. The chicks developed sarcomas. The causative agent in the liquid was a virus, now called Rous sarcoma virus (RSV).

Later work by others showed that RSV was a type of retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...

. Non-cancer-forming retroviruses contain three genes, called gag, pol, and env. Some tumor-inducing retroviruses (such as RSV), however, also contain a gene called v-src (viral-sarcoma). It was found that the v-src gene in RSV is required for the formation of cancer and that the other genes have no role in oncogenesis.

A function for Src tyrosine kinases in normal cell growth was first demonstrated with the binding of family member p56lck to the cytoplasmic tail of the CD4 and CD8 co-receptors on T-cells. Src tyrosine kinases also transmit integrin
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...

-dependent signals central to cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 movement and proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

. Hallmarks of v-src induced transformation are rounding of the cell and the formation of actin rich podosome
Podosome
Podosomes are small cylindrical ECM adhesion structures approximately 0.5 um in diameter. They contain focal contact proteins like vinculin and paxillin and are found primarily in malignant cells. They can also be found in normal cells such as macrophages and osteoclasts...

s on the basal surface of the cell. These structures are correlated with increased invasiveness, a process thought to be essential for metastasis.

v-src lacks the C-terminal
C-terminal end
The C-terminus is the end of an amino acid chain , terminated by a free carboxyl group . When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus...

 inhibitory phosphorylation site (tyrosine-527), and is therefore constitutively active as opposed to normal src (c-src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-src is therefore an instructive example of an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...

 whereas c-src is a proto-oncogene.

The first sequence of v-src was published in 1980 and the characterization of sites for tyrosine phosphorylation in the transforming protein of Rous sarcoma virus and its normal cellular homologue was published in 1981.

c-src

In 1979, J. Michael Bishop
J. Michael Bishop
-External links:**...

 and Harold E. Varmus
Harold E. Varmus
Harold Elliot Varmus is an American Nobel Prize-winning scientist and the 14th and current Director of the National Cancer Institute, a post he was appointed to by President Barack Obama. He was a co-recipient Harold Elliot Varmus (born December 18, 1939) is an American Nobel Prize-winning...

 discovered that normal chickens contain a gene that is structurally closely related to v-src. 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
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

 into an abnormally functioning oncogene within the Rous sarcoma virus
Rous sarcoma virus
Rous sarcoma virus is a retrovirus and is the first oncovirus to have been described: it causes sarcoma in chickens.As with all retroviruses, it reverse transcribes its RNA genome into cDNA before integration into the host DNA.-History:...

. Once the oncogene is transfected back into a chicken, it can lead to cancer.

src: The transforming
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 (sarcoma inducing) gene of Rous sarcoma virus. The protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 product is pp60vsrc, a cytoplasmic protein with tyrosine-specific protein kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...

 activity , that associates with the cytoplasmic face of the plasma membrane. The protein consists of three domains, an N-terminal SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...

, a central SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...

 and a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

 domain. The SH2 and SH3 domains cooperate in the auto-inhibition of the kinase domain. c-Src is phosphorylated on an inhibitory tyrosine near the c-terminus of the protein. This produces a binding site for the SH2 domain which, when bound, facilitates binding of the SH3 domain to a low affinity polyproline site within the linker between the SH2 domain and the kinase domain. Binding of the SH3 domain results in misalignment of residues within the kinase domain's active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...

 inactivating the enzyme. This allows for multiple mechanism for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase
Protein tyrosine phosphatase
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular...

, binding of the SH2 domain by a competitive phospho-tyrosine residue, as seen in the case of c-Src binding to focal adhesion kinase, or competitive binding of a polyproline binding site to the SH3 domain, as seen in the case of the HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

 NEF protein.

Interactions

Src (gene) has been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with
  • AR
    Androgen receptor
    The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...

    ,
  • ARNT
    Aryl hydrocarbon receptor nuclear translocator
    The ARNT gene encodes the aryl hydrocarbon receptor nuclear translocator protein that forms a complex with ligand-bound aryl hydrocarbon receptor , and is required for receptor function. The encoded protein has also been identified as the beta subunit of a heterodimeric transcription factor,...

    ,
  • AHR
    Aryl hydrocarbon receptor
    The Aryl hydrocarbon receptor is a member of the family of basic-helix-loop-helix transcription factors. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones...

    ,
  • ADRBK1
    Beta adrenergic receptor kinase
    Beta adrenergic receptor kinase is a serine/threonine intracellular kinase. It is activated by PKA and its target is the beta adrenergic receptor...

    ,
  • ADRB3
    Beta-3 adrenergic receptor
    The beta-3 adrenergic receptor , also known as ADRB3, is an beta-adrenergic receptor, and also denotes the human gene encoding it.-Function:Actions of the β3 receptor include:*Enhancement of lipolysis in adipose tissue....

    ,
  • BCAR1
    BCAR1
    Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the BCAR1 gene.-External links:* Info with links in the...

    ,
  • CD44
    CD44
    The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene.- Tissue distribution and isoforms :...

    ,
  • DAB2
    DAB2
    Disabled homolog 2 is a protein that in humans is encoded by the DAB2 gene.-Interactions:DAB2 has been shown to interact with C-src tyrosine kinase, Cdk1, Src, LRP2, DVL3, PIN1, MYO6, DVL2, DAB2IP, Mothers against decapentaplegic homolog 3 and Mothers against decapentaplegic homolog 2.-Further...

    ,
  • DDEF1
    DDEF1
    Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 is a protein that in humans is encoded by the ASAP1 gene.-Interactions:DDEF1 has been shown to interact with Src.-Further reading:...

    ,
  • DAG1
    Dystroglycan
    Dystroglycan is a protein that in humans is encoded by the DAG1 gene.Dystroglycan is one of the dystrophin-associated glycoproteins, which is encoded by a 5.5 kb transcript in Homo sapiens by chromosome 3. There are two exons that are separated by a large intron...

    ,
  • EPHB2
    EPH receptor B2
    Ephrin type-B receptor 2 is a protein that in humans is encoded by the EPHB2 gene.Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system...

    ,
  • EGFR
    Epidermal growth factor receptor
    The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...

    ,
  • EPS8
    EPS8
    Epidermal growth factor receptor kinase substrate 8 is an enzyme that in humans is encoded by the EPS8 gene.-Interactions:EPS8 has been shown to interact with BAIAP2, SHB, Src, SOS1, DVL1, SHC1 and ABI1.-Further reading:...

    ,
  • ESR1
    Estrogen receptor alpha
    Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...

    ,
  • ESR2
    Estrogen receptor beta
    Estrogen receptor beta , also known as NR3A2 , is a nuclear receptor which is activated by the sex hormone estrogen. In humans, ER-β is encoded by the ESR2 gene.- Function :...

    ,
  • GNB2L1
    GNB2L1
    Guanine nucleotide-binding protein subunit beta-2-like 1 is a protein that in humans is encoded by the GNB2L1 gene.-Interactions:GNB2L1 has been shown to interact with PDE4D, STAT1, Tyrosine kinase 2, Src, Androgen receptor, AGTRAP, Janus kinase 1, FYN, Cyclin A1, IFNAR2, PRKCE, P73, RAS p21...

    ,
  • GRB2
    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....

    ,
  • GRIN2A
    GRIN2A
    Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene.-Interactions:GRIN2A has been shown to interact with FYN, DLG4, DLG3, DLG1, Src, PTK2B and Interleukin 16.-Further reading:...

    ,
  • HNF1A
    HNF1A
    HNF1 homeobox A , also known as HNF1A, is a human gene.The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes.-Interactions:HNF1A has been shown to interact with PCAF, Src,...

    ,
  • KHDRBS1
    KHDRBS1
    KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.-Further reading:...

    ,
  • MT-ND2,
  • MUC1
    MUC1
    Mucin 1, cell surface associated or polymorphic epithelial mucin is a mucin encoded by the MUC1 gene in humans. MUC1 is a proteoglycan with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and...

    ,
  • NCOA6
    NCOA6
    Nuclear receptor coactivator 6 is a protein that in humans is encoded by the NCOA6 gene.-Interactions:NCOA6 has been shown to interact with Ku70, RBBP5, E2F1, Retinoblastoma protein, CREB-binding protein, Activating transcription factor 2, HSF1, HBXIP, TGS1, TUBB, TUBA4A, Thyroid hormone receptor...

    ,
  • PDE6G
    PDE6G
    Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma is an enzyme that in humans is encoded by the PDE6G gene.-Interactions:PDE6G has been shown to interact with Beta adrenergic receptor kinase and Src.-External links:...

    ,
  • PLD2
    PLD2
    Phospholipase D2 is an enzyme that in humans is encoded by the PLD2 gene.-Interactions:PLD2 has been shown to interact with BIN1, Amphiphysin, Aldolase A, PLCG1, ARF1, Src, PRKCD, Glyceraldehyde 3-phosphate dehydrogenase ,Caveolin 1,and Wiskott-Aldrich syndrome protein.-Inhibitors:* N--2-naphthamide:...

    ,
  • PRKCZ,
  • PTK2
    PTK2
    PTK2 protein tyrosine kinase 2 , also known as Focal Adhesion Kinase , is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes...

    ,
  • PTK2B
    PTK2B
    Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.-Protein:-Interactions:PTK2B has been shown to interact with PTPN11, PTPN6, PITPNM1, Gelsolin, Src, GRIN2A, Ewing sarcoma breakpoint region 1, RB1CC1, TGFB1I1, NPHP1, BCAR1, FYN, DLG4, DLG3, DDEF2, Cbl gene, RAS...

    ,
  • RAF1
    C-Raf
    RAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...

    ,
  • RASA1
    RAS p21 protein activator 1
    RAS p21 protein activator 1 or RasGAP , also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:...

    ,
  • RARA
    Retinoic acid receptor alpha
    Retinoic acid receptor alpha , also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.- Function :...

    ,
  • RICS
    RICS (gene)
    Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene. RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi...

    ,
  • SRF
    Serum response factor
    Serum response factor , also known as SRF, is a transcription factor.It is a member of the MADS box superfamily of transcription factors. This protein binds to the serum response element in the promoter region of target genes...

    ,
  • SHB
    SHB (gene)
    SH2 domain-containing adapter protein B is a protein that in humans is encoded by the SHB gene.-Interactions:SHB has been shown to interact with Fibroblast growth factor receptor 1, Src, Linker of activated T cells, Lymphocyte cytosolic protein 2, ZAP-70, EPS8, PIK3R1 and VAV1.-Further reading:...

    ,
  • STAT1
    STAT1
    STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...

    ,
  • STAT3
    STAT3
    Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...

    , and
  • WAS.

External links

- interactive 3D model of the structure of SRC
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