Integrins as regulators of the mitotic machinery

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Mitotic spindle bipolarity defines a unique division plane that promotes the successful transmission of genetic material during cytokinesis. The positioning and orientation of the spindle determines the symmetry of cell division and the relative location of daughter cells, which regulate cell fate decisions that contribute to embryonic development and tissue differentiation. Recent studies have identified integrins as regulators of spindle positioning and orientation, as well as spindle bipolarity and cytokinesis. This review summarizes and discusses the current effort focused on understanding how integrins regulate these mitotic events.

Introduction

The proper assembly and function of the mitotic spindle is essential for the segregation and transmission of genetic material [1]. Defects in chromosome segregation can lead to lethal errors that result in birth defects and contribute to tumor development. The assembly of the mitotic spindle is a complex process involving tightly regulated centrosome duplication, enhanced microtubule (Mt) nucleation, increased Mt dynamics, and the association of Mts with the cell cortex and kinetochores [2, 3, 4]. Spindle bipolarity is important for chromosome congression in metaphase and segregation in anaphase and contributes to cytokinesis by regulating the assembly of the contractile ring and the ingression of the cleavage furrow [5]. The positioning and orientation of the mitotic spindle are also important as they define the division plane, which contributes to embryonic development and tissue differentiation by determining the relative location of daughter cells and the differential inheritance of cytoplasmic determinants.

Increasing interest has focused on integrins as regulators of mitotic events. Integrins form a large family of α/β heterodimeric receptors that mediate cell adhesion to components of the extracellular matrix [6]. Integrin-mediated adhesion activates signals that regulate a number of cellular processes including cell migration, proliferation, and differentiation [6, 7, 8].

Integrin β subunit cytoplasmic domains (β tails) are central to integrin function. Integrin activity is conformationally regulated by proteins that bind to the β tail [9]. The adhesive function of integrins requires their ability to form transmembrane links with the actin cytoskeleton and β tails mediate this connection [10, 11, 12, 13]. Additionally, integrins activate intracellular-signaling proteins, such as the cytoplasmic tyrosine kinases FAK and Src, the Rho family of GTPases, including RhoA, Rac1, and Cdc42, and the lipid kinase, phosphatidylinositol-3-OH kinase (PI 3-kinase). β tails regulate signaling by many of these proteins [14, 15, 16, 17], which are also known to control the actin and Mt cytoskeletons [18].

Here we review recent studies linking integrins to the mitotic machinery, providing a new paradigm for integrin signaling. Our discussion aims to provide a framework to understand how integrins can influence the assembly and positioning of the mitotic spindle, as well as cytokinesis.

Section snippets

Spindle positioning and orientation

The identification of mechanisms that control the positioning and orientation of the mitotic spindle has interested biologists for decades. The ability of integrins to regulate cortical cues that position the mitotic spindle was first suggested by studies in NRK cells [19•]. In these cells, the spindle axis aligns parallel to the long axis of the cell. When cell shape (and therefore cell adhesion) was experimentally changed during mitosis, the spindle was repositioned in the direction of new

Integrin signaling and astral microtubules

The interaction of astral Mts with specific regions of the cell cortex contributes to positioning the spindle at mitosis. The mechanisms involved may be similar to those used by integrins to regulate Mt dynamics during cell migration [31]. End-binding protein1 (EB1) and adenomatous polyposis coli (APC) bind to the plus end of Mts to promote their growth and association with the cell cortex during both processes [25••, 32, 33]. The interaction of APC with Mts is inhibited when it becomes

Bipolar spindle assembly and cytokinesis

In a recent study, CHO cells expressing chimeric integrins that mediate adhesion to fibrinogen (Fg) [10, 43] were used as a model system to demonstrate that the integrin β1 cytoplasmic tail regulates cell division [44••]. A tyrosine-to-alanine substitution in the membrane-proximal NPIY motif of the β1 tail (Y783A) known to perturb integrin function [45] dramatically inhibited the formation of the bipolar spindle and cytokinesis [44••]. Importantly, these phenotypes were not cell-type-specific

In vivo models

Currently, there are two examples in which the integrin-regulation of the mitotic machinery in mammalian cells has physiological consequences. In mouse chondrocytes, the conditional deletion of the β1 gene resulted in the accumulation of binucleated chondrocytes with age, suggesting defects in cytokinesis; these mice also developed chondrodysplasia [53•]. Conditional deletion of the β1 gene in basal keratinocytes caused defects in spindle positioning. In these cells, the mitotic spindle

Conclusions and perspectives

The identification of integrins as regulators of mitotic events provides a new paradigm in integrin signaling. The mechanisms by which integrins regulate these events are just beginning to be unraveled. Most progress has been made in understanding how integrins regulate spindle positioning and orientation. Dissecting the mechanisms by which integrins promote spindle bipolarity may not be a trivial task as this process is more complex. Furthermore, integrins may initiate several signaling events

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank Drs Yu-Li Wang and Fumiko Toyoshima for helpful discussions and Ms Debbie Moran for assistance in the preparation of the figures. Work from the LaFlamme laboratory was supported by grant GM51540 to SEL from the National Institute of Health.

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