*4.3. Potential Significance for the Long Splice Variants in Other Processes and Diseases*

TRIOBP-5 and/or 6 are known to be expressed in the brain alongside TRIOBP-1 [4,5], and TRIOBP-5 exogenously expressed in neurons forms aggregates similar to those of TRIOBP-1 [23]. It is therefore possible that aggregation of longer TRIOBP isoforms may play a role in mental illness, but this remains to be investigated.

*TRIOBP-5* and/or *6* was also seen to be upregulated in a pancreatic cancer cell line, distinct from another cell line that expressed *TRIOBP-4* in the same study [45]. Curiously, knockdown of *TRIOBP-5*/*6* in these cells led to reorganization of the actin cytoskeleton and inhibition of filopodia formation [45]. This implies the existence of a more general role for TRIOBP-5/6 in actin dynamics, of potential relevance for cancer. This may occur through its actin binding sites in either repeat region R1 shared with TRIOBP-4, its central coiled coil domain shared with TRIOBP-1, or a combination. One piece of evidence arguing for a TRIOBP-4-like mechanism is that, in a wound healing assay, knockdown of *TRIOBP-5*/*6* led to reduced cell motility, but this could be rescued through expression of TRIOBP-4 [45]. However, TRIOBP-5/6 was also seen, along with TRIOBP-1, to have its expression inhibited by the metastasis suppressing microRNA *miR-3178*, suggesting that a TRIOBP-1-like role of the longer isoforms also exists, and is of relevance to cancer [46].
