Transgelin-2 and phosphoregulation of the LIC2 subunit of dynein regulate mitotic spindle orientation

Most cells divide through a highly dynamic but tightly regulated process known as mitosis to help the body grow and develop properly. Mistake(s) during mitosis lead to aberrant growth and development, and often to deadly diseases like cancer. One key event early during mitosis is the proper positioning and orientation of the mitotic spindle within the mother cell, a process crucial to decide the proper axis of body growth, organ development and maintenance of stem cells. The mitotic spindle largely consists of thread-like dynamic microtubules that radiate outward from the two nucleating centres at its two ends, the “spindle poles”. To properly orient the spindle within the mother cell, similar to a hammock being properly tied between two trees, sufficient numbers of microtubules must nucleate and radiate outward from each pole, and then be “captured” by proteins resident at the cell boundary (cortex), thus anchoring the spindle to the cortex. The intracellular transport motor vehicle dynein, a ubiquitous multi-protein assembly present both on spindle poles and at the cortex, is indispensable for both these processes of microtubule nucleation and cortical capture to orient the spindle.

In a study recently published in the Journal of Cell Science (2020), we have identified two new mechanisms used by the dynein motor to orient the mitotic spindle. First, we showed that a specific biochemical modification (phosphorylation at amino acid residue 194) of the LIC2 protein component of dynein must occur in the mitotic cell for the spindle poles to remain intact and sprout sufficient numbers of microtubules. Second, we discovered a new interaction accomplice of dynein located at the cell boundary (cortex), transgelin-2. We show that transgelin-2 helps maintain proper levels of two well-known cortically located, microtubule capturing proteins, LGN and NuMA, thereby helping to properly “lasso” the mitotic spindle to the cell boundary. This is thus a new function discovered for transgelin-2, which was otherwise known to help string together the fibrous actin skeleton of the cell at the cortex. Interestingly, this new dynein-transgelin-2 association is also mediated through the LIC2 subunit but independent of its phosphorylation status, and exclusively in mitotically dividing cells.

Our study suggests that the functions of dynein in ensuring proper spindle orientation and cell division are more intricately regulated than so far known. To ensure proper cell division, dynein, essentially an intracellular “motor vehicle”, associates with a wide spectrum of cargo “passengers”, but in a highly selective manner due to its tight regulation. This study highlights the indispensable role of the LIC2 subunit as a vital mediator of dynein’s cargo binding selectivity. Of relevance to human health, these observations reveal novel molecular targets and interfaces for potential therapeutic intervention strategies against diseases and disorders caused by aberrant cell division.

Dr. Sivaram V. S. Mylavarapu, Laboratory of Cell Division, Intercellular Communication and Cellular Dynamics

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