Key Points
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v-src was the first of numerous viral oncogenes to be identified and is among the best studied of these. The cellular counterpart of this oncogene — c-SRC — is implicated in a range of human cancers.
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Both overexpression and overactivation of c-SRC can promote the development of cancer. The structural mechanisms by which c-SRC kinase activity is regulated are now well established, and c-SRC is known to have a negative-regulatory domain that is itself regulated through phosphorylation.
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c-SRC kinase activity is regulated by several mechanisms, including activation by receptor tyrosine kinases and cytoplasmic phosphatases. Levels of c-SRC protein can also be regulated, for example, by targeting this protein for degradation in the ubiquitin–proteasome pathway. In addition, c-SRC function can also be modulated by regulation of its cellular localization.
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A wide range of c-SRC substrates have been identified, which has led to a better understanding of c-SRC-mediated signal transduction. These substrates include focal-adhesion proteins, adaptor proteins and transcription factors.
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In addition to cell proliferation, SRC proteins regulate three main cellular functions that ultimately control the behaviour of transformed cells: adhesion, invasion and motility. These functions might also contribute to tumour progression and metastasis.
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Recently, drug-discovery efforts have led to the development of several c-SRC inhibitors for potential use as anticancer therapeutics.
Abstract
The c-SRC non-receptor tyrosine kinase is overexpressed and activated in a large number of human malignancies and has been linked to the development of cancer and progression to distant metastases. These observations have led to the recent targeting of c-SRC for the development of anticancer therapeutics, which show promise as a new avenue for cancer treatment. Despite this, however, the precise functions of c-SRC in cancer remain unclear. In addition to increasing cell proliferation, a key role of c-SRC in cancer seems to be to promote invasion and motility, functions that might contribute to tumour progression.
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The author thanks R. Jove for his critical comments.
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FURTHER INFORMATION
Glossary
- SH DOMAINS
-
SRC homology domains are distinct regions of amino-acid homology that possess well-defined biochemical functions.
- MYRISTOYLATION
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Refers to the accession of fatty moieties that allow association with the inner layer of the plasma membrane.
- LAMELLIPODIA
-
Thin, sheet-like cell extensions of cytoplasm found at the leading edge of crawling cells. They form transient adhesions with the cell substrate, enabling the cell to move along a surface.
- FILOPODIA
-
Small membrane projections, rich in actin, which emanate from the leading edge of the cell in the direction of movement.
- G PROTEINS
-
GTP-binding intracellular-membrane-associated proteins that are activated by receptor stimulation.
- DENSITY INHIBITION
-
The process by which non-transformed cells limit their proliferation when a certain density is reached due to physical contact with other cells or colonies.
- CADHERINS
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A group of functionally related glycoproteins that are involved in calcium-dependent cell-to-cell adhesion.
- SELECTINS
-
A family of cell-adhesion molecules consisting of a lectin-like domain, an epidermal growth-factor-like domain, and a variable number of domains that are homologous to complement-binding proteins. Selectins mediate the binding of leukocytes to the vascular endothelium.
- METALLOPROTEINASES
-
A group of enzymes that can break down extracellular matrix proteins and require zinc or calcium atoms for catalytic activity. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumour-cell metastasis.
- TIMPs
-
Tissue inhibitors of metalloproteinases are a family of secreted proteins that have a crucial role in regulating the activity of metalloproteinases. They influence the activation of the pro-metalloproteinase and act to modulate proteolysis of the extracellular matrix, notably during tissue remodelling and inflammatory processes.
- INVADOPODIA
-
Invadopodia are specialized plasma-membrane structures associated with invading cells and extracellular-matrix degradation. These cellular protrusions are enriched in integrins and their associated tyrosine-kinase signalling molecules, metalloproteinases, and actin and actin-associated proteins.
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Yeatman, T. A renaissance for SRC. Nat Rev Cancer 4, 470–480 (2004). https://doi.org/10.1038/nrc1366
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DOI: https://doi.org/10.1038/nrc1366
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