Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7

Kremer, B. E. et al., Cell 130, 837-850. (2007)

Speaker: 張筱琦                             Time: 14:00-15:00, Nov. 21, 2007

Commentator: 林秋烽 老師                   Place: Room 601

Abstract

Septins (SEPT) are conserved GTP–binding proteins in all eukaryotes except plants.  In mammalian cells, there are at least 13 septins that may be involved in mitosis and cytokinesis.  SEPT9 modulates actin dynamics in Rho signaling, linking membrane receptors to actin cytoskeleton.  The SEPT2/6/7 complex regulates the microtubule cytoskeleton and associates with actin stress fibers (1).  However, the biological relevance of interaction between mammalian septins and the actin cytoskeleton is still lacking.  In this paper, the authors found that knockdown of SEPT2, 6, and 7 by siRNAs resulted in the dissolution of actin stress fibers and loss of cell polarity.  This effect was triggered by nuclear accumulation of an adapter protein NCK, which coordinates receptor tyrosine kinases, focal adhesion, and the actin cytoskeleton (2).  The suppressor of cytokine signaling 7 (SOCS7) interacted with NCK and mediated the nuclear transport of NCK in septin-depleted cells.  Septins bound to SOCS7 and sequestered NCK in the cytoplasm.  Endogenous NCK was occasionally present in the nucleus and the SEPT2/6/7 complex reorganized during cell division, suggesting that septins may be involved in cell cycle regulation through NCK.  Interestingly, they found that UV irradiation induced phenomenons that were similar to septin depletion, including nuclear accumulation of NCK, which was necessary for cell-cycle arrest.  Furthermore, following UV irradiation, the DNA damage sensor kinases ATM and ATR were efficiently activated in the nck^-/- cells.  However, the levels of phosphorylated CHK2 and p53, downstream molecules of ATM, were decreased in these NCK-null cells.  Taken together, these data suggest a novel link between mammalian septins and actin via SOCS7/NCK signaling that couples the regulation of DNA damage responses to the cytoskeleton.

References

1.      Spiliotis, E.T., and Nelson, W.J. Here come the septins: novel polymers that coordinate intracellular functions and organization. J. Cell Sci. 119: 4–10. (2006)

2.      Buday, L., Wunderlich, L., and Tamas, P. The Nck family of adapter proteins: regulators of actin cytoskeleton. Cell. Signal. 14: 723–731. (2002)