Proteolysis and cell migration: creating a path?

doi:10.1016/S0955-0674(99)00022-8

Current Opinion in Cell Biology

Volume 11, Issue 5, 1 October 1999, Pages 614-621

https://doi.org/10.1016/S0955-0674(99)00022-8 Get rights and content

Abstract

Both serine and metalloproteinases have been implicated in the complex integrated events underlying cell migration but no definitive single mechanism has emerged. Work over the past two years linking both membrane and soluble proteinases with integrins and other adhesion proteins and with intracellular signalling systems could herald the beginnings of a potential expansion of our understanding of the role and regulation of proteolysis in cell migration.

Introduction

Cell migration plays a key role in a plethora of biological events including morphogenesis, wound healing and tumour metastasis. The molecular mechanisms behind the various cellular strategies employed are being analysed at all levels, from interactions between the cell and its extracellular matrix (ECM), cytoskeletal changes, cell signalling and gene regulation. The efficient integration of these processes is a key determinant of different cell migration patterns and a major challenge to a rational understanding of events 1, 2. The migration of different cell types is determined by variables such as their origin, adhesion receptor function and the environment, including the nature of the ECM. In vivo the movement of cells within or through tissue barriers is clearly a complex process, and can only provide us with some of the clues to the precise mechanisms involved, but two-dimensional or three-dimensional migration/invasion models set up in vitro can help to establish some of the basic principles. The major question is ‘Do cells always use proteolytic mechanisms to modify the ECM in their path and is this simply a path clearing mechanism, or a way of reorganising the matrix to facilitate cellular interactions?’. The further implications of matrix degradation also cannot be ignored, including the release of growth factors, and the generation of modulatory neo-epitopes.

Early studies placed most emphasis on the role of the urokinase-type plasminogen activator, (uPA), system and plasmin generation in the facilitation of cell migration [3], but the contribution of matrix metalloproteinases (MMPs) has become evident more recently [4]. Evidence that the two systems interact has also emerged, although no single mechanism can be defined (Table 1). Some cell types express proteinases when they simply bind to an ECM or during reorganisation and contraction of a three-dimensional matrix and this is likely to be of relevance to cell migration processes 5, 6, 7•, 8, 9•, 10, 11, 12.

Section snippets

The uPA system

It has long been hypothesized that cells might focus proteinases at their leading edge, where proteolysis can direct migration, but this has been technically challenging to demonstrate. The plasmin cascade system driven by uPA operates by this type of mechanism, as the uPA receptor (uPAR) was shown to be spatially and temporally associated with cellular structures that regulate cell adhesion, migration and invasion, colocalising with integrins in focal contacts and at the leading edge of

The role of matrix metalloproteinases

MMPs have been implicated in the remodelling of the ECM and the penetration of both normal and tumour cells through tissue barriers, although no definitive single mechanism can be ascribed to all situations. A role for MMPs in VSMC migration has been convincingly demonstrated by the overexpression of TIMPs (tissue inhibitors of MMPs) in the vascular wall in vivo 21, 22 and in vitro 23, 24. Although these studies provide evidence that MMPs are involved in VSMC migration through the ECM, as yet

MMP modification of matrix: effects on cell migration

The question of what variety of functions cell surface localised MMP2 may have, besides ‘creating a path’, is also of importance. Giannelli et al. [59] reported that exogenous MMP2 induces the migration of breast epithelial cells on laminin 5. MMP2 specifically cleaved the α2 subunit of laminin 5 exposing a putative cryptic pro-migratory site that triggered cell motility.

Recent studies suggest that modification of the basal lamina of the endoneurium is essential to peripheral nerve regeneration

Conclusions and future directions

The concept that cells focus proteolytic activities at their cell surface to help remove ECM barriers to migration, or to promote detachment, is upheld by the recent data emerging in this area. The next year should see the development of studies relating cell-surface proteinases with the cytoskeleton and with cellular signalling activities. A promising key area of research in this regard is the uPA receptor–caveolin–integrin interactions and their consequences. The role of growth factors with

Acknowledgements

We are indebted to Vera Knäuper for drawing the figures and to Jill Gorton for manuscript preparation. Our research is funded by the Medical Research Council, the Wellcome Trust, the Arthritis Research Campaign and the British Heart Foundation. Due to the limited number of citations permitted, we apologise to all those whose work is not featured.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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ReviewProteolysis and cell migration: creating a path?

Abstract

Introduction

Section snippets

The uPA system

The role of matrix metalloproteinases

MMP modification of matrix: effects on cell migration

Conclusions and future directions

Acknowledgements

References and recommended reading

Cell

Curr Opin Cell Biol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Curr Opin Cell Biol

Cell

Thromb Res

Cell

J Biol Chem

J Invest Dermatol

J Biol Chem

J Biol Chem

J Biol Chem

Mol Cell

Exp Cell Res

Cell

Cell

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cell migration strategies in 3-D extracellular matrix: differences in morphology, cell matrix interactions, and integrin function

Microsc Res Tech

The urokinase-type plasminogen activator system in cancer metastasis: a review

Int J Cancer

Implication of collagen type 1-induced membrane-type 1 matrix metalloproteinase expression and matrix metalloproteinase-2 activation in the metastatic progression of breast carcinoma

Lab Invest

Remodeling of collagen matrix by human tumor cells requires activation and cell surface association of matrix metalloproteinase-2

Cancer Res

Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change

Science

Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through β1 integrin

Cancer Res

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Nat Med

Emerging roles for proteinases in cancer

Invasion Metastasis

Proteinase requirements of epidermal growth factor-induced ovarian cancer cell invasion

Int J Cancer

Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor- and scatter factor-stimulated invasion of carcinoma cells

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Review
Proteolysis and cell migration: creating a path?