Skip to main content
  • Viewpoint
  • Published:

New insights into integrin signalling: implications for rheumatoid arthritis synovial fibroblasts

Introduction

Fibronectin is an important component of the articular extracellular matrix (ECM). Both fibronectin itself and fragments of fibronectin bind to integrin receptors on mesenchymal cells and exert a variety of effects. Of these, regulation of cell growth, migration and survival are most prominent. However, it has also been demonstrated that injection of fibronectin fragments into joints may cause depletion of proteoglycans [1] and induce the production of matrix degrading enzymes [2, 3]. Binding of fibronectin to integrin receptors results in the activation of tyrosine phosphorylation signals, and it is now accepted that the focal adhesion-associated tyrosine kinase (FAK) plays a central role in this process. Interactions of FAK with the src family of protein tyrosine kinases (Src-PTKs) have been described as being crucial for the initiation of signalling cascades that ultimately mediate the effects of integrins. Despite this general concept, early molecular events that regulate the association of FAK with Src-PTKs and thus link integrin signalling to cellular activation are unclear. Specifically, little is known about the role of receptor protein tyrosine phosphatases (PTPs), which have been implicated as positive and negative regulators of integrin signalling.

A recent report from Zeng and coworkers [4] sheds new light on the involvement of PTPs in early integrin signalling. Autophosphorylation of FAK at Tyr397 is a key initial step in the formation of Src-PTK/FAK complexes, which in turn mediate the phosphorylation of FAK associated proteins. The establishment of this multi-phosphocomponent signalling complex appears to be regulated by several intracellular PTPs, one of which is PTP-α. PTP-α can be found in focal adhesions and is involved in the spreading of cells on fibronectin. As shown in earlier studies, expression of PTP-α correlates with Src-PTK activity, and PTP-α acts as a physiological upstream regulator of Scr-PTKs [5].

Zheng and coworkers [4] compared wild-type, normal PTP-α+/+ and PTP-α-/- mouse embryonic fibroblasts with respect to their nonspecific cell migration as well as haptotactic migration toward fibronectin. In addition, they analyzed the effects of PTP-α on integrin-mediated FAK phosphorylation. Those investigators observed abnormalities of PTP-α-/- embryonic fibroblasts in migrating into space on cell culture dishes. They showed that the migratory defects of PTP-α-/- fibroblasts are associated with altered cell morphology at the leading edge of migrating cells. These changes are linked to reduced FAK Tyr397 phosphorylation during closure of artificial wounds. Their finding that the haptotaxis of immortalized embryonic fibroblasts to fibronectin critically depends on PTP-α is of special interest. Fibronectin-induced rearrangement of the cytoskeleton is retarded in PTP-α-/- cells, but reintroduction of PTP-α through adenoviral gene transfer partly restores the migration of PTP-α-/- toward fibronectin. Although no data on the expression of PTP-α following gene transfer are presented, the authors suggest that the lower levels of PTP-α protein in AdPTP-α transduced PTP-α-/- fibroblasts as compared with wild-type PTP-α+/+ cells are responsible for the incomplete effects of adenoviral delivery of PTP-α. Importantly, fibronectin-induced association of FAK with Scr-PTKs is reduced also in PTP-α-/- fibroblasts. The association of FAK with Src-PTKs depends on the autophosphorylation status of FAK. Therefore, the phosphorylation of FAK at Tyr397 in PTP-α-/- fibroblasts was investigated; FAK Tyr397 phosphorylation in response to fibronectin-induced integrin activation is impaired in the PTP-α-/- cells but can be restored by expression of catalytically active PTP-α. Of interest, the delay in cell spreading and the altered morphology of PTP-α-/- cells were reproduced by addition of Src-PTK inhibitors.

Based on these data, Zheng and coworkers concluded that FAK Tyr397 phophorylation is an early event in integrin signalling and is mediated by PTP-α. Defects in PTP-α activity result in the impaired formation of Src-PTK/FAK complexes and affect cytoskeletal rearrangement, cell spreading and haptotaxis to ECM molecules. However, FAK interacts with different members of Src-PTK family, and the precise nature of these interactions requires further investigation. In addition, the question of how PTP-α acts as an Scr-PTK activator should now be addressed. Nevertheless, these data highlight the role played by PTP-α as a key upstream regulator of integrin-mediated signalling, linking ECM signals to cell migration and Src-FAK signalling.

Integrin-mediated signal transduction is of considerable interest in a variety of conditions that are associated with altered attachment of fibroblasts-like cells to ECM. In rheumatoid arthritis (RA), attachment of synovial fibroblast to the ECM is an important initiating step in the progressive destruction of articular cartilage [6]. Following early morphological observations [7], several studies have established the notion that the invasion of RA synovial fibroblasts (SFs) into articular cartilage requires their attachment to the cartilage surface. Integrins have been identified as important receptors for ECM molecules in RA, and the increased expression of integrins on RA-SFs has been associated with their enhanced binding to ECM [8]. Functional data support the concept that integrin-mediated signalling events contribute to the invasiveness of RA-SFs [9]. In addition, cartilage-specific fragments of fibronectin have been identified as potent activators of articular chondrocytes [3, 10] and fibroblasts [11]. However, little is known about regulation of integrin signalling in RA-SFs and the relevance of Src-PTK/FAK formation for synovial cell activation. This is in striking contrast to the multitude of data illustrating the importance of cytokine-mediated activation, as well as accumulating evidence for stable alterations in the intracellular signalling of RA-SFs. Thus, a recent study linked cytokine-mediated expression of vascular cell adhesion molecule-1 in RA-SFs to Src-dependent pathways [12], and data have been reported that suggest that inhibition of Src-PTKs suppresses RA-SF proliferation and interleukin-6 production [13]. In addition, PTEN, a tyrosine phosphatase that interacts with FAK and negatively regulates integrin-mediated cell spreading, is not expressed in RA-SFs of the most superficial lining layer and at sites of invasion [14].

It is intriguing to speculate that alterations in Src-PTK/FAK complex formation are present in RA-SFs, and it is clear that this aspect of fibroblasts activation requires further attention. By focusing on cytoskeletal rearrangement and cell migration, Zeng and coworkers [4] address only part of the several pathways that have been linked to Src and FAK signalling and that are of interest for enhancing our understanding the complex nature of activated RA-SF behaviour. This paper, together with data suggesting a role for Src-FAK signalling in tumour cell metastasis [15], should stimulate studies focusing on the role of FAK-mediated signalling, and specifically the role of PTPs, in RA-SFs.

Note

This article is based on papers highlighted by Faculty of 1000 http://www.facultyof1000.com/start.asp, a web-based literature awareness service. Faculty of 1000 evaluations available for articles cited in this report may be viewed on our website at: http://arthritis-research.com

Abbreviations

ECM:

extracellular matrix

FAK:

focal adhesion-associated tyrosine kinase

PTP:

protein tyrosine phosphatase

RA:

rheumatoid arthritis

SF:

synovial fibroblast

Src-PTK:

src protein tyrosine kinase.

References

  1. Homandberg GA, Meyers R, Williams JM: Intraarticular injection of fibronectin fragments causes severe depletion of cartilage proteoglycans in vivo. J Rheumatol. 1993, 20: 1378-1382.

    CAS  PubMed  Google Scholar 

  2. Yasuda T, Shimizu M, Nakagawa T, Julovi SM, Nakamura T: Matrix metalloproteinase production by COOH-terminal heparin-binding fibronectin fragment in rheumatoid synovial cells. Lab Invest. 2003, 83: 153-162.

    Article  CAS  PubMed  Google Scholar 

  3. Yasuda T, Poole AR: A fibronectin fragment induces type II collagen degradation by collagenase through an interleukin-1-mediated pathway. Arthritis Rheum. 2002, 46: 138-148. 10.1002/1529-0131(200201)46:1<138::AID-ART10051>3.0.CO;2-K.

    Article  CAS  PubMed  Google Scholar 

  4. Zeng L, Si X, Yu WP, Le HT, Ng KP, Teng RM, Ryan K, Wang DZ, Ponniah S, Pallen CJ: PTPα regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J Cell Biol. 2003, 160: 137-146. 10.1083/jcb.200206049. For the Faculty of 1000 evaluation of this article please see: http://arthritis-research.com/reports/ar4_03.asp

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Su J, Muranjan M, Sap J: Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr Biol. 1999, 9: 505-511. 10.1016/S0960-9822(99)80234-6.

    Article  CAS  PubMed  Google Scholar 

  6. Pap T, Müller-Ladner U, Gay RE, Gay S: Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2000, 2: 361-367. 10.1186/ar113.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Fassbender HG: Histomorphological basis of articular cartilage destruction in rheumatoid arthritis. Coll Relat Res. 1983, 3: 141-155.

    Article  CAS  PubMed  Google Scholar 

  8. Rinaldi N, Schwarz-Eywill M, Weis D, Leppelmann-Jansen P, Lukoschek M, Keilholz U, Barth TF: Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann Rheum Dis. 1997, 56: 45-51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Wang AZ, Wang JC, Fisher GW, Diamond HS: Interleukin-1beta-stimulated invasion of articular cartilage by rheumatoid synovial fibroblasts is inhibited by antibodies to specific integrin receptors and by collagenase inhibitors. Arthritis Rheum. 1997, 40: 1298-1307.

    Article  CAS  PubMed  Google Scholar 

  10. Arner EC, Tortorella MD: Signal transduction through chondrocyte integrin receptors induces matrix metalloproteinase synthesis and synergizes with interleukin-1. Arthritis Rheum. 1995, 38: 1304-1314.

    Article  CAS  PubMed  Google Scholar 

  11. Wang AZ, Zhang XR, Wang JC, Fisher GW, Diamond HS: Fibronectin induces protease dependent focal matrix depletion and cell overlap in cultured rheumatoid synoviocytes. J Rheumatol. 1995, 22: 817-828.

    CAS  PubMed  Google Scholar 

  12. Morel JC, Park CC, Zhu K, Kumar P, Ruth JH, Koch AE: Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin-18-induced vascular cell adhesion molecule-1 expression. J Biol Chem. 2002, 277: 34679-34691. 10.1074/jbc.M206337200.

    Article  CAS  PubMed  Google Scholar 

  13. Takayanagi H, Juji T, Miyazaki T, Iizuka H, Takahashi T, Isshiki M, Okada M, Tanaka Y, Koshihara Y, Oda H, Kurokawa T, Nakamura K, Tanaka S: Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J Clin Invest. 1999, 104: 137-146.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Pap T, Franz JK, Hummel KM, Jeisy E, Gay RE, Gay S: Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res. 2000, 2: 59-65. 10.1186/ar69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Hauck CR, Hsia DA, Puente XS, Cheresh DA, Schlaepfer DD: FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. EMBO J. 2002, 21: 6289-6302. 10.1093/emboj/cdf631.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thomas Pap MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pap, T. New insights into integrin signalling: implications for rheumatoid arthritis synovial fibroblasts. Arthritis Res Ther 5, 154 (2003). https://doi.org/10.1186/ar765

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/ar765

Keywords