ANLN

Anillin has a unique multi-domain structure. At the N-terminus, there is an actin- and myosin-binding domain. At the C-terminus, there is a PH domain. The PH domain is conserved and essential for anillin functionality. There are also numerous anillin-like protein homologues found outside of metazoans. In Schizosaccharomyces pombe (fission yeast), there are Mid1p and Mid2p. These two anillin-like proteins do not have any overlap in their functions. Mid1p has been characterized as a key regulator in cytokinesis, responsible for arranging contractile ring assembly and positioning. Mid2p acts later in cytokinesis to organize septins during septation, or the invagination of inner membranes, outer membranes, and the cell wall that occurs in order to separate daughter cells completely. Saccharomyces cerevisiae (budding yeast) also have two anillin-like proteins, Boi1p and Boi2p. Boi1p and Boi2p localize to the nucleus and contractile ring at the bud neck, respectively. They are essential for cell growth and bud formation. == Function ==

Anillins are required for the faithfulness of cytokinesis and its F-actin-, myosin-, and septin-binding domains implicate anillin in actomyosin cytoskeletal organization. In agreement with this belief, anillin-mutant cells have disrupted contractile rings. Additionally, it is hypothesized that anillin couples the actomyosin cytoskeleton to microtubules by binding MgcRacGAP/CYK-4/RacGAP50C. Anillins have also been shown to organize the actomyosin cytoskeleton into syncytial structures observed in Drosophila embryos or C. elegans gonads. ANI-1 and ANI-2 (proteins homologous to anillin) are essential for embryonic viability in both organisms. ANI-1 is required for cortical ruffling, pseudocleavage, and all contractile events that occur in embryos prior to mitosis. ANI-1 is also crucial for segregation of polar bodies during meiosis. ANI-2 functions in the maintenance of the structure of the central core of the cytoplasm, the rachis, during oogenesis. ANI-2 ensures oocytes do not disconnect prematurely from the rachis, thereby leading to the generation of embryos of varying sizes. In vitro experiments suggest that anillin drives myosin-independent actin contractility. ==Binding Partners==

Actin Anillin specifically binds F-actin, rather than G-actin. Binding of F-actin by anillin only occurs during cell division. Anillin also bundles actin filaments together and drives their relative sliding. Myosin Anillin interacts directly with non-muscle myosin II and interacts indirectly with myosin via F-actin. Residues 142-254 (near the N-terminus) are essential for anillin binding myosin in Xenopus. The interaction of anillin and myosin is also dependent on phosphorylation of the myosin light chain. The interaction of myosin and anillin does not seem to serve in recruitment, but rather organization of myosin. In Drosophila, anillin is necessary to organize myosin into rings in the cellularization front. Depletion of anillin in Drosophila and humans leads to changes in the spatial and temporal stability of myosin during cytokinesis. In C. elegans, ANI-1 organizes myosin into foci during cytokinesis and establishment of polarity, whereas, ANI-2 is a requirement for the maintenance of myosin-rich contractile lining of oogenic gonads. The direct interaction between anillin and septins was first shown by the interaction seen between Xenopus anillin and a minimal reconstituted heterooligomer of human septins 2, 6, and 7. The ability of anillin to bind to septins is dependent on the C-terminal domain, which contains a terminal PH domain and an upstream sequence known as the “Anillin Homology” (AH) domain. Cyk-4 Drosophila anillin interacts with Cyk-4, a central spindle protein, indicating that anillin may have a role in determining the division plane during cytokinesis. In anillin-depleted larval cells, the central spindle does not extend to the cortex. Human anillin-depleted cells show improperly positioned and distorted central spindles. Microtubules Anillin was first isolated from Drosophila by harnessing its interactions with both F-actin and microtubules. Furthermore, anillin-rich structures that form after Latrunculin A treatment of Drosophila cells localize to the plus-ends of microtubules. The interaction between anillin and microtubules suggest that anillin may serve as a signaling factor to relay the position of the mitotic spindle to the cortex to ensure appropriate contractile ring formation during cytokinesis. ==Regulation==

Anillins in metazoans are heavily phosphorylated; however, the kinases responsible for the phosphorylation are unknown at the present time. In humans and Drosophila, anillins are recruited to the equatorial cortex in a RhoA-dependent manner. This recruitment is independent of other cytoskeletal Rho targets such as myosin, F-actin, and Rho-kinase. It has been observed that anillin proteolysis is triggered after mitotic exit by the Anaphase Promoting Complex (APC). Most anillins can be sequestered to the nucleus during interphase, but there are exceptions – Drosophila anilins in the early embryo, C. elegans ANI-1 in early embryos, C. elegans ANI-2 in oogenic gonads, and Mid2p in fission yeast. These anillins that are not sequestered during interphase suggest that anillins may also regulate cytoskeletal dynamics outside the contractile ring during cytokinesis. ==Role in Diseases==

Anillin is critical for cell division and therefore development and homeostasis in metazoans. In recent years, the expression levels of anillin have been shown to correlate to the metastatic potential of human tumours. In colorectal cancer, expression levels of anillin are higher in tumours and when anillin was over-expressed in HT29 cells, a classical colorectal cancer cell line, the cells showed faster replication kinetics due to the lengthening of G2/M phase. Increasing the expression of anillin also led to further invasiveness and migration of numerous colorectal cancer cell lines. The hypothesis from such observations is that anillin promotes EMT and cell migration through cytoskeletal remodeling, leading to enhanced proliferation, invasion, and mobility of tumour cells. == References ==