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  • Review Article
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Closing in on the biological functions of fps/fes and fer

Nature Reviews Molecular Cell Biology volume 3, pages 278–289 (2002)Cite this article

Key Points

  • The fps/fes (Fujinami poultry sarcoma/feline sarcoma) and fer (Fes-related protein) proto-oncogenes encode distinct members of the non-receptor/cytoplasmic protein-tyrosine kinase family. Retroviral fps/fes alleles encode Gag–Fps/Fes fusion proteins, which are constitutively active kinases that can cause cellular transformation in vitro and tumours in vivo. The role of cellular Fps/Fes and Fer kinases is still unclear.

  • Cellular Fps/Fes and Fer kinases consist of an amino-terminal Fps/Fes/Fer/CIP4 homology (FCH) domain — which might have a role in microfilament association — followed by three regions of predicted coiled-coils (which seem to regulate oligomerization), a central Src-homology-2 (SH2) domain (which mediates association with phosphotyrosine-containing peptide motifs) and a carboxy-terminal catalytic domain.

  • Transgenic overexpression of retroviral or activated mutant fps/fes alleles resulted in several malignancies and hyperplasias in some tissues. These observations underscored the potential involvement of Fps/Fes in human cancer and indicate roles for regulation of cellular proliferation.

  • Fps/Fes and Fer kinases are implicated in signalling downstream of the receptors for several cytokines, growth factors and immunoglobin (Ig)-receptors; however, the precise molecular roles are not well understood. Some recent observations of Fps/Fes and Fer activation downstream from IgE receptors on mast cells and the glycoprotein VI collagen receptor on platelets indicates that they might serve redundant biochemical roles.

  • Studies using targeted germ-line null or loss-of-function mouse models of Fps/Fes have shown that this kinase is not required for haematopoiesis. However, many subtle phenotypes show an involvement that might be redundant with another kinase. This is further supported by more pronounced defects in mice that lack both Fps/Fes and Fer kinase activities.

  • Other studies with targeted mouse models show that both Fps/Fes and Fer are involved in the regulation of inflammatory responses and innate immunity. Mice that lack either Fps/Fes or Fer kinase activity show enhanced sensitivity to endotoxin challenge and defects in the regulation of inflammatory cell functions, including mast-cell migration and leukocyte extravasation.

  • Although the molecular functions of Fps/Fes and Fer kinases are still unknown, there is mounting evidence for a role in regulation of cell–cell and cell–matrix interactions, possibly through regulating rearrangement of the cytoskeleton and cross-talk between integrins and other receptor systems, such as adherens junctions or receptors for growth factors and cytokines.

Abstract

Fps/Fes and Fer are the only known members of a distinct subfamily of the non-receptor protein-tyrosine kinase family. Recent studies indicate that these kinases have roles in regulating cytoskeletal rearrangements and inside–out signalling that accompany receptor–ligand, cell–matrix and cell–cell interactions. Genetic analysis using transgenic mouse models also implicates these kinases in the regulation of inflammation and innate immunity.

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Figure 1: Structural organization of cellular and viral Fps/Fes and cellular Fer proteins.
Figure 2: FCH domain-containing proteins.
Figure 3: Putative models of Fps/Fes and Fer regulation.
Figure 4: A model of the Fer SH2 and catalytic domains based on the solved structures of related PTKs.
Figure 5: Hypothetical involvement of Fer in crosstalk between different receptor systems.
Figure 6: Possible involvement of Fer and Fps/Fes in crosstalk between different receptors systems.

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Acknowledgements

I thank E. Leinala and Z. Jia for assistance with the modelled Fer structure, and A. Craig, W. Sangrar, Y. Senis, R. Zirngibl, N. Peterson, D. Lee, P. Truesdell and S. Parsons for critical comments about this article and for personal communication of unpublished results. Our research programme is supported by grants from the Canadian Institutes of Health Research and the National Cancer Institute of Canada with funds from the Canadian Cancer Society.

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  1. Division of Cancer Research and Genetics, Queen's University Cancer Research Institute, Kingston, K7L 3N6, Ontario, Canada

    Peter Greer

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DATABASES

Interpro

FCH

SH2

SH3

LocusLink

PDGF receptor

Swiss-Prot

Abl

BCR

β-catenin

CD3ɛ

CD72

CIP4

connexin 43

cortactin

EGF receptor

ezrin

Fer

ferT

FGF2

fps/fes

fur

Fyb/SLAP130

G-CSF

GM-CSF

GPVI

Grb2

Hck

IL-1α

IL-3

IL-4

IL-5

IL-6

IL-10

IL-11

IRS-1

IRS-2

LAR-PTP

leukaemia inhibitory factor

Lyn

N-cadherin

Nck

oncostatin M

p120catenin

p130Cas

p62Dok

p120RasGAP

p190RhoGAP

PTP-α

PTP1B

PTP-PEST

PU.1

Rac1

SOS

STAT3

STAT5A

TNF-α

WASP

FURTHER READING

Pawson web site protein module resource

Protein kinase web site

Simple Modular Architecture Research Tool web site

Glossary

GAG

The protein of the nucleocapsid shell around the RNA of a retrovirus.

ADHERENS JUNCTION

A cell–cell adhesive junction that is linked to cytoskeletal filaments of the microfilament type.

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.

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

HAEMATOPOIETIC PROGENITOR CELL

A stem cell that gives rise to blood cells.

LYMPHOID TISSUE

The vertebrate tissue in which white blood cells develop.

MESENCHYMAL TISSUE

Tissue that is comprised of loosely organized, undifferentiated connective tissue, and is typically present in the early embryo.

TRIGEMINAL NERVE

The fifth vertebrate peripheral nerve that emerges from within the skull. It is sensory from the head, but motor to the jaw muscles.

MYELOID LINEAGE

Cells that are derived from the bone marrow.

TERMINAL DIFFERENTIATION

Changes that lead to the acquisition of a mature functional phenotype.

MYELOPOIESIS

The formation of granulocytes and monocytes from myeloid progenitor cells.

PACHYTENE

The third stage of the prophase of meiosis, during which the homologous chromosomes become short and thick, and divide into four distinct chromatids.

CRE

Cre is a site-specific recombinase that recognizes and binds to specific sites called loxP. Two loxP sites recombine at nearly 100% efficiency in the presence of Cre, which allows DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

SH3 DOMAIN

(Src-homology-3 domain.) A protein sequence of about 50 amino acids that recognizes and binds sequences that are rich in proline.

ADAPTOR PROTEIN

A protein that augments cellular responses by recruiting other proteins to a complex. It usually contains several protein–protein-interaction domains.

AUTOPHOSPHORYLATION

The phosphorylation by a protein of one of its own residues.

RHO FAMILY GTPase

A Ras-related GTPase that is involved in controlling the polymerization of actin.

CRK

An adaptor protein, which was first described as the product of an avian oncogene, v-Crk. It contains an amino-terminal SH2 domain and two SH3 domains that function as binding sites for a diverse set of signalling proteins.

ACTIVATION LOOP

A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.

MACROPHAGE

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

B-LYMPHOMA

A cancer that originates from uncontrolled proliferation of B-lymphocytes.

MYRISTOYLATION

The covalent attachment of a hydrophobic myristoyl group to the amino-terminal glycine residue of a nascent polypeptide.

HEMANGIOMA

A benign skin lesion, which consists of dense, usually elevated, masses of dilated blood vessels.

CARDIOMEGALY

Enlargement of the heart.

SPLENOMEGALY

Enlargement of the spleen.

NEUTROPHIL

A phagocytic cell of the myeloid lineage, which has an important role in the inflammatory response, and undergoes chemotaxis towards sites of infection or wounding.

LIPOPOLYSACCHARIDE

A component of the outer membrane of Gram-negative bacteria that is made of a lipid, a core oligosaccharide and an O-linked sugar side chain.

ENDOTOXAEMIC SHOCK

Shock induced by the response to endotoxaemia, a condition in which toxic substances that are associated with certain bacteria — endotoxins — access the bloodstream.

MICROARRAY ANALYSIS

The analysis of either genomic or cDNA samples by hybridization, which enables the quantitation of the amount of different nucleic acid molecules that are present in a sample of interest.

UBIQUITYLATION

The attachment of the protein ubiquitin to lysine residues of other molecules, often as a tag for their rapid cellular degradation.

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.

ENDOSOME

An organelle that carries materials ingested by endocytosis, and passes them to lysosomes for degradation or recycles them to the cell surface.

MAST CELL

A type of leukocyte of the granulocyte subclass.

TROJAN PEPTIDES

Peptides that are based on the ability of derivatives of the Penetratin 1 peptide — which is extracted from the third helix of the homeodomain of Antennapedia — to cross cell membranes with a remarkable efficiency.

DEGRANULATION

The process by which perforin-filled granules are released when a cytotoxic T cell or natural killer cell contacts its target (typically a tumour cell).

ENTEROCOLITIS

A condition in which the small intestine and the colon are inflamed.

EXTRAVASATION

The process that describes how a cell or a substance can pass between two endothelial cells of a blood vessel into the surrounding tissue.

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.

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Greer, P. Closing in on the biological functions of fps/fes and fer. Nat Rev Mol Cell Biol 3, 278–289 (2002). https://doi.org/10.1038/nrm783

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