Emerging role for nuclear rotation and orientation in cell migration

Abstract

Nucleus movement, positioning, and orientation is precisely specified and actively regulated within cells, and it plays a critical role in many cellular and developmental processes. Mutation of proteins that regulate the nucleus anchoring and movement lead to diverse pathologies, laminopathies in particular, suggesting that the nucleus correct positioning and movement is essential for proper cellular function. In motile cells that polarize toward the direction of migration, the nucleus undergoes controlled rotation promoting the alignment of the nucleus with the axis of migration. Such spatial organization of the cell appears to be optimal for the cell migration. Nuclear reorientation requires the cytoskeleton to be anchored to the nuclear envelope, which exerts pulling or pushing torque on the nucleus. Here we discuss the possible molecular mechanisms regulating the nuclear rotation and reorientation and the significance of this type of nuclear movement for cell migration.

Keywords: FAK; LINC; actin; cell polarity; dynein; focal adhesions; microtubules; migration; myosin; nuclear reorientation.

Figure 1. Schematic representation of an adherent migrating cell with front-rear polarity. Polarized cell displays conical shape with actin polymerization induced at the leading edge (pink) and limited at the cell rear. Cells are attached to the substrate through cell–matrix adhesion, such as focal contacts and adhesions, which connects extracellular matrix to cellular cytoskeleton. (A) In polarized cells, the oval-shaped nucleus localizes to the cell rear, MTOC in front of the nucleus close to the cell center, and microtubules are preferentially oriented toward the leading edge and they are stabilized at this location. The relative position of the nucleus and MTOC is an important marker of cell migration polarity defining the axis of migration. In addition, the longer nuclear axis is aligned with the axis of migration. (B) Specific types of actin filaments anchored to the dorsal side of the nucleus contribute to the establishment of asymmetric profile of the migrating cell. TAN lines are arranged perpendicular to axis of migration and drive the rearward movement of the nucleus during cell polarization. Perinuclear actin cap fibers span the nucleus and link the nucleus to subset of focal adhesions at cell periphery. Actin cap filaments are aligned with the axis of migration and longer nuclear axis and they probably stabilize nuclear orientation. It is not clear whether perinuclear actin cap and TAN lines co-exist in the same cell.

Figure 2. Schematic representation of hypothetical nuclear reorientation models. Forces exerted and transmitted by the cell cytoskeleton (black arrows) are transferred to the nucleus through LINC complex (not shown) to induce nucleus rotation and reorientation (red arrows). (A and B) Microtubules induce nuclear reorientation by forces exerted by microtubule-associated motor protein dynein. (A) Dynein pulls at the tips and alongside of microtubules to induce MTOC re-positioning close to the cell center (yellow arrow). Because MTOC associates with the nucleus, MTOC movement also induces nucleus reorientation (red arrows). (B) Dynein, through its interactions with nesprins, links microtubules to the nuclear envelope and pulls the nucleus as a huge cargo toward minus end of microtubules mediating nuclear reorientation. The asymmetric distribution of microtubules associated with nucleus is required to induce torque on the nucleus. (C) Actin cap fibers reorientate the nucleus. Actin cap fibers emanating from the focal adhesions at the leading edge associate with LINC complex at the nuclear envelope, predominantly at one pole of the nucleus. Nuclear reorientation is induced by actomyosin contractile forces between the leading edge and the nucleus.

Figure 3. Signaling pathways involved in the regulation of nuclear reorientation. Two signaling pathways that converge at small GTPase Rho regulate cycling between active (GTP-bound) and inactive (GDP-bound) state of Rho allowing the cytoskeleton remodeling and subsequently nuclear reorientation. LPA signaling induces the activation of heterotrimeric G proteins, and consequently, RGS-RhoGEF, such as p115–RhoGEF, which directly activates Rho. Since LPA is a soluble mitogen it presumably activates Rho within cell uniformly. Active Rho regulates the stabilization of pre-existing cytoskeletal filaments that anchor the nucleus in immobile state (box A). Acute integrin engagement to ECM at the cell front activates FAK/Src signaling complex that recruits Rho inhibitor p190RhoGAP to the leading edge. Transient Rho inhibition at the leading edge leads to the destabilization of cytoskeletal filaments and consequent asymmetry in cytoskeletal forces may induce nucleus reorientation (box B). Since integrin-mediated Rho inactivation is transient, new cycle of Rho activation allows re-assembly and stabilization of new cytoskeletal filaments oriented toward the leading edge that may pull the nucleus and contribute to the nucleus reorientation (box C).