Research from the University of Kent's School of Biosciences and the University of Manchester has uncovered an essential mechanism coordinating the processes of cell division and adhesion within humans. This discovery has profound potential for advancing understanding of cell adhesion signalling in cancerous tumour progression and metastasis.

The research, published in the Journal of Biological Chemistry, identifies the long sought link within the cell cycle between the mechanism for cell division, the proliferation that enables all living organisms to function and regenerate, and the cell adhesion that holds them in the correct position within the organism's structure.

For cell division to occur inside humans, the cell must release its adhesions to the surroundings at the exact moment the cell starts to divide. This synchronisation of the cell adhesion and the cell cycle is critical for the correct functioning of cells in tissues and to prevent uncontrolled cell division in processes such as cancer.

Researchers found that CDK1, the master regulator of the cell cycle binds directly to, and modifies, the core protein talin that is essential to the process of cell adhesion. This interaction represents a coupling of the cell proliferation and adhesion processes. This indicates a unifying mechanism by which the processes of cell division and adhesion are controlled.

Discovering the initial mechanism of this vital process in the tissues of humans is the first-step in a new branch of understanding health issues relating to the cell cycle, including cancerous tumours.

Dr Ben Goult, Reader in Biochemistry at the University of Kent and a Principal Investigator of the paper said: 'The potential of this discovery is huge as it provides a new understanding of how cell division is coordinated within the confines of a complex multicellular organism. Cell division needs to be tightly coupled to the cell adhesion to allow our cells to divide without disrupting the integrity of our tissues and organs. This research is vital in our understanding of other cellular diseases and of cancer's ability to spread within the human body.'

This research was funded by the Biotechnology and Biological Sciences Research Council, the Human Frontiers Science Program and Cancer Research UK.

Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.

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