Background:We showed that nuclear tyrosine phosphorylation is involved in chromatin structural changes. Results: Several tyrosine kinases phosphorylate KAP1 at Tyr-449, Tyr-458, and Tyr-517 in the nucleus, resulting in a decrease of KAP1 association with heterochromatin. Conclusion: Tyrosine phosphorylation of KAP1 by nucleus-localized tyrosine kinases, including Src, involves heterochromatin structural changes. Significance: These findings provide a new insight into nuclear tyrosine phosphorylation signals.

No abstract

Background: Mimosine is a cell synchronization reagent used for arresting cells in late G 1 and S phases. Results: Replication fork assembly is reversibly blocked by ATM activation through mimosine-generated reactive oxygen species. Conclusion: Mimosine induces cell cycle arrest strictly at the G 1 -S phase boundary, which prevents replication fork stallinginduced DNA damage. Significance: These findings provide a novel mechanism of the mimosine-induced G 1 checkpoint.

Background: Tyrosine kinases are active in the cell nucleus and involved in global nuclear structure. Results: Phosphorylation of AKAP8 at multiple tyrosine residues by several nucleus-localized tyrosine kinases, including c-Src, induces AKAP8's dissociation from nuclear structures. Conclusion: Nuclear tyrosine phosphorylation of AKAP8 is involved in global nuclear structure changes. Significance: These findings highlight the importance of nuclear tyrosine phosphorylation in dynamic chromatin regulation.

Proper resolution of inflammation is vital for repair and restoration of homeostasis after tissue damage, and its dysregulation underlies various noncommunicable diseases, such as cardiovascular and metabolic diseases. Macrophages play diverse roles throughout initial inflammation, its resolution, and tissue repair. Differential metabolic reprogramming is reportedly required for induction and support of the various macrophage activation states. Here we show that a long noncoding RNA (lncRNA),lncFAO, contributes to inflammation resolution and tissue repair in mice by promoting fatty acid oxidation (FAO) in macrophages.lncFAOis induced late after lipopolysaccharide (LPS) stimulation of cultured macrophages and in Ly6Chimonocyte-derived macrophages in damaged tissue during the resolution and reparative phases. We found thatlncFAOdirectly interacts with the HADHB subunit of mitochondrial trifunctional protein and activates FAO.lncFAOdeletion impairs resolution of inflammation related to endotoxic shock and delays resolution of inflammation and tissue repair in a skin wound. These results demonstrate that by tuning mitochondrial metabolism,lncFAOacts as a node of immunometabolic control in macrophages during the resolution and repair phases of inflammation.

Src-family tyrosine kinases, which are expressed in various cell types, play critical roles in cell signalling at the cytoplasmic side of the plasma membrane through their lipid modifications. Src-family kinases are cotranslationally myristoylated and posttranslationally palmitoylated in the amino-terminal region. The Src-family member Lyn contains a myristoylation site at glycine-2 and a palmitoylation site at cysteine-3, whereas c-Src has a myristoylation site at glycine-2 but not any palmitoylation sites. However, little is known about the role for lipid modifications of Src-family kinases in cell division. Here, we show that non-lipid-modified Lyn and c-Src, Lyn(G2A/C3A) and c-Src(G2A), are delocalized from membranes to the cytoplasm and the nucleus, which gives rise to a significant increase in the rate of chromosome missegregation, such as chromosome lagging and anaphase chromosome bridging, in a tyrosine kinase activity-dependent manner. Treatment with the Src inhibitor PP2 shows that the kinase activity of non-lipid-modified, non-membrane-bound Src during M phase is critical for giving rise to chromosome missegregation. Given that only a fraction of Src-family kinases fails in lipid modifications during biosynthesis, these results suggest that Src’s membrane anchorage through their lipid modifications from prophase to anaphase plays a protective role against induction of chromosome missegregation.

No abstract

The mitotic spindle is the major piece of cellular machinery essential for faithful chromosome segregation. Whereas Fyn, a member of Src-family kinases, is known to be localized to the meiotic and mitotic spindle microtubules, the role of Fyn in mitotic spindle formation has not yet been completely elucidated. In this study, we studied the role of Fyn in spindle formation and effects on M-phase progression. Re-expression of Fyn induced increases in the fluorescence intensity of mitotic spindle microtubules in SYF cells having triple knock-out mutations of c-Src, c-Yes, and Fyn. Cold treatment results showed that Fyn increases the maximum length of microtubules in HeLa S3 cells in a manner dependent on Fyn kinase activity. Complete depolymerization of microtubules under cold treatment and the following release into 37 °C revealed that the increase in the microtubule length in Fyn-expressing cells may be attributed to the promotion of microtubule polymerization. After cold treatment, Fyn promotes the accumulation of EB1, which is a plus-end tracking protein and facilitates microtubule growth, in a manner dependent on the kinase activity. Furthermore, Fyn accelerates the M phase progression of cells from nocodazole arrest. These results suggest that Fyn facilitates mitotic spindle formation through the increase in microtubule polymerization, resulting in the acceleration of M-phase progression.