A study provides new insight into the regularity mechanisms behind the perinuclear actin cap, a key regulator of nuclear morphology. Led by Professor Angeliki Malliri, findings of the study have recently been published in Nature Communications.

Migration of cells is important for many normal physiological processes – such as wound healing – but it is also required for cancers to spread.  When cancer cells invade, they often have to squeeze through tight spaces between tissues, which requires correct orientation of the cell nucleus, the largest structure within the cell.  By using individual cell tracking, scientists from the Cell Signalling group have shown that loss of STEF reduces cell migration, and that STEF (also known as Tiam2) localises to the outer membrane of the nucleus.

In cells plated onto micropatterns, which force them to take on a migrating shape, the long axis of the nucleus tends to align with the front of the cell.  STEF depleted cells show a disruption of this nuclear orientation.  Adding STEF back to the cells restores normal orientation, but not when using a version of STEF which is unable to activate Rac1.  Rac1 regulates actin, which forms long cable-like structures within the cell.  Cells depleted for STEF have fewer actin cables specifically above the nucleus; this ‘actin cap’ regulates nuclear orientation and stiffness.  The researchers were able to restore the actin cap in cells lacking STEF by specifically targeting an activated form of Rac1 (which no longer requires STEF) to the outer nuclear membrane.

Using Atomic Forces Microscopy, the scientists showed that this lack of actin cables in STEF depleted cells led to reduced nuclear stiffness, which in turn increased nuclear height.  The researchers showed that this also affected signalling within the cell, including through the HIPPO pathway, which is often deregulated in cancer. 

Image: STEF-depleted cell showing nucleus (blue) with active Rac1 (green) targeted to the nuclear membrane where it has restored the cables of the actin cap (red).  Outline of the cell shown in magenta.

Publication:

Woroniuk A, Porter A, White G, Newman DT, Diamantopoulou Z, Waring T, Rooney C, Strathdee D, Marston DJ, Hahn KM, Sansom OJ, Zech T, Malliri A. (2018) STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap. Nat Commun. 9(1):2124.