Depletion of PAK1 enhances Ubiquitin-mediated Survivin degradation in pancreatic β-cells

Abstract

Functional β-cell mass deficiency in diabetes results from imbalanced β-cell death and replication, and decreased PAK1 protein levels in human islets from donors with type 2 diabetes implicates a possible role for PAK1 in maintaining β-cell mass. Here, we aim to address the linkage between PAK1 and Survivin, a protein essential for β-cell replication. PAK1 knockout (KO) mouse islets exhibited decreased expression of Survivin protein. MIN6 β-cells with siRNA-mediated suppression of PAK1 also had decreased Survivin protein and exhibited an increased level of ubiquitinated-Survivin. However, no significant changes in Survivin mRNA were found in islets from PAK1 KO mice and PAK1-depleted MIN6 β-cells. The decreased Survivin level in MIN6 cells subjected to hyperglycemic stress was prevented by expression of exogenous PAK1. Moreover, overexpressing Survivin restored proliferation of β-cells that was impaired by the loss of PAK1. These data implicate a role for PAK1 in regulating Survivin protein stability in the β-cell and suggest PAK1 as a potential molecular target for the restoration of β-cell mass.

The role of quantitative changes in the epxression of insulin receptor substrate-1 and nuclear ubiquitin in abnormal glycometabolism in the livers of KKay mice and the relative therapeutic mechanisms of Astragalus polysaccharide

“…Increasing evidence has indicated that the ubiquitinproteasome system participates in the regulation of insulin signaling (26)(27)(28), and there have been several studies published on the transcriptional and post-transcriptional regulation of this system in the nucleolus (29)(30)(31). In our study, the results from immunohistochemistry revealed that the overexpression of ubiquitin in the hepatic nucleolus significantly correlated with the onset of insulin resistance and type 2 diabetes, when comparing the DG and IG mice with the CG mice.…”

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

“…Since survivin is highly expressed in malignant cells, but not in normal cells, survivin could be a selective target for anti-cancer drugs. Interestingly, in 2013 a group at Indiana University found that PAK1-deficiency in mice inactivates survivin gene [51], clearly indicating that PAK1 is essential for transcription of survivin gene. Furthermore, we found that PAK1-deficient mutant of nematode (RB689) lives 60% longer than the wild-type [5], strongly suggesting the possibility that YM-155 could also extend the …”

Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis <i>in ovo</i> (fertilized eggs) <i>via</i> their common PAK1-survivin/VEGF signaling pathway

“…First of all, these in ovo observations altogether have proven that both 15K and YM155 exert their potent anti-angiogenic activity by blocking their common oncogenic/angiogenic PAK1-survivin signaling pathway, as PAK1 is essential for survivin expression (10), and the potent survivin-suppressor YM155 indeed blocks PAK1 as well as AKT in cancer cells (9,11). To the best of our knowledge, both 15K and YM155 are the most potent anti-angiogenic PAK1-blockers so far.…”

“…This is not a great surprise because it has been known that PAK1-deficient mice express far less survivin, clearly indicating that PAK1 is essential for survivin expression (10). Interestingly, however, YM155 blocks AKT by inhibiting epithelial growth factor (EGF) receptor (11).…”