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v-SRC'S hold over actin and cell adhesions

Abstract

The oncoprotein v-Src and its cellular homologue (c-Src) are tyrosine kinases that modulate the actin cytoskeleton and cell adhesions. Through the concerted action of their protein-interaction and kinase domains, they are targeted to cell–matrix integrin adhesions or cadherin-dependent junctions between epithelial cells, where they phosphorylate substrates that induce adhesion turnover and actin re-modelling. Recent experiments have defined some of the key targets and effector pathways that mediate the pleiotropic oncogenic effects of v-Src.

Key Points

  • v-Src was the first identified tyrosine kinase and the first known oncoprotein. It is located in adhesion sites at the plasma membrane, from where it induces pleiotropic effects on cells that result in the transformed phenotype.

  • The intracellular targeting of v-Src, and c-Src, in mesenchymal cells is dependent on actin stress fibres and peripheral actin re-modelling that is, in turn, controlled by the Rho family of small GTPases.

  • The non-catalytic domains of Src — SH3 (modulated also by SH2) domains — are essential for proper intracellular targeting, and are mediated by interaction with protein partners, such as PI3K. In addition, the adaptor functions of Src might also have a role in the assembly of adhesion signalling complexes after integrin engagement.

  • The result of the unrestrained catalytic activity of v-Src at adhesion sites is to induce adhesion turnover and disorganization of the associated actin cytoskeleton. When this is unregulated in primary cells, the result is complete loss of cell-substratum adhesion and detachment. In established cell lines, the result is enhanced adhesion turnover that facilitates rapid cell migration. This is in keeping with the evidence that the Src family kinases have a key role in integrin-dependent cell motility.

  • v-Src-induced activation of the calcium-dependent protease, calpain, and tyrosine phosphorylation of focal adhesion kinase (FAK), lead to FAK proteolysis, events that are associated with adhesion disruption in transformed cells.

  • v-Src also induces actin re-modelling, and specifically induces formation of actin-rich podosomes that contain several regulators of actin assembly, including cortactin, that is a v-Src substrate. In addition, v-Src induces tyrosine phosphorylation of p190 Rho-GAP that might mediate stress-fibre disorganization by antagonizing the actin assembly function of RhoA.

  • v-Src activity at the cell periphery also triggers intracellular signalling that promotes cell-cycle progression, and specifically induces rapid transit through the pRb checkpoint at the G1/S boundary. Surprisingly, calpain activity is required also for the cell–cycle changes that are induced by the oncprotein.

  • The catalytic activity of v-Src, and c-Src in epithelial cells results in disruption of cadherin-mediated cell-cell adhesions. Although this is not yet well understood in molecular terms, new potential Src effectors at adherens junctions are being identified. Weakened cadherin-dependent adhesions might be an important consequence of elevated Src activity in epithelial cancers.

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Figure 1: v-Src transformation.
Figure 2: Adhesion stabilization by kinase-defective v-Src.
Figure 3: Calpain and cell migration.
Figure 4: Calpain proteolysis of FAK.
Figure 5: EGFR and calpain.
Figure 6: Calpain mediates Src-induced growth and de-adhesion.

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Correspondence to Margaret C. Frame.

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DATABASES

Interpro

SH2

SH3

LocusLink

FAK

<i>Saccharomyces</i> Genome Database

VPS34

Swiss-Prot

E-cadherin

calpain 1

calpain 2

calpain 4

calpain 6

calpastatin

β-catenin

Cdk2

Cdk4

Cdk6

c-Src

EGF

EGFR

Fyn

GFP

Grb2

myosin light chain kinase

N-WASP

paxillin

p27Kip1

p85 regulatory subunit of PI3K

p190 RhoGAP

Rac1

RhoA

R-Ras

Yes

Glossary

FOCAL ADHESIONS

Focal adhesions are cellular structures that link the extracellular matrix on the outside of the cell, through integrin receptors, to the actin cytoskeleton inside the cell.

PHALLOIDIN

A family of toxins that is present in the highly poisonous agaric fungus, Amanita phalloides. Phalloidin binds specifically to actin filaments and prevents their depolymerization.

MOTOGENIC

An effect that stimulates the locomotory phenotype.

CADHERINS

Calcium-dependent adhesion molecules that mediate homophilic adhesions. There are several subfamilies of cadherin.

STRESS FIBRES

Axial bundles of F-actin that underlie the cell bodies, which are typically induced by the activity of the GTPase RhoA.

MYRISTOYLATION

Covalent attachment of a hydrophobic myristoyl group to an amino-terminal glycine residue of a nascent polypeptide.

LAMELLIPODIA

Flattened, sheet-like structures, which are composed of a crosslinked F-actin meshwork, that project from the surface of a cell. They are often associated with cell migration.

FILOPODIA

Long, thin protrusions at the periphery of cells and growth cones. They are composed of F-actin bundles.

PHORBOL ESTERS

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, and thereby irreversibly activate protein kinase C.

MACROPHAGE

Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

OSTEOCLAST

A multinucleate macrophage that has the capacity to erode bone-matrix and is therefore important in bone remodelling.

METALLOPROTEINASE

A proteinase that has a metal ion at its active site.

EPITHELIAL–MESENCHYMAL TRANSITION

The conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

PSEUDOPOD

A temporary projection of the cytoplasm of certain cells, such as phagocytes, or of certain unicellular organisms, especially amoebas, that serves in locomotion and phagocytosis.

MITOGENIC

An effect that stimulates or induces mitosis.

CYCLIN-DEPENDENT KINASE

An enzyme that phosphorylates target proteins that are involved in DNA synthesis and mitosis. It requires a cyclin partner for activity and substrate specificity.

ADHERENS JUNCTIONS

Cell–cell adhesive junctions that are linked to cytoskeletal filaments of the microfilament type.

E3 UBIQUITIN PROTEIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, and thereby coordinate ubiquitylation of the selected substrates.

E2F FAMILY OF TRANSCRIPTION FACTORS

A family of six proteins that regulate expression of genes that are required for DNA replication.

KERATINOCYTES

Differentiated epithelial cells of the skin.

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Frame, M., Fincham, V., Carragher, N. et al. v-SRC'S hold over actin and cell adhesions. Nat Rev Mol Cell Biol 3, 233–245 (2002). https://doi.org/10.1038/nrm779

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