Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K–Akt signaling

Abstract

Phosphoinositide-3 kinase (PI3K)/Akt signaling is activated by growth factors such as insulin and epidermal growth factor (EGF) and regulates several functions such as cell cycling, apoptosis, cell growth, and cell migration. Here, we find that Kank is an Akt substrate located downstream of PI3K and a 14-3-3–binding protein. The interaction between Kank and 14-3-3 is regulated by insulin and EGF and is mediated through phosphorylation of Kank by Akt. In NIH3T3 cells expressing Kank, the amount of actin stress fibers is reduced, and the coexpression of 14-3-3 disrupted this effect. Kank also inhibits insulin-induced cell migration via 14-3-3 binding. Furthermore, Kank inhibits insulin and active Akt-dependent activation of RhoA through binding to 14-3-3. Based on these findings, we hypothesize that Kank negatively regulates the formation of actin stress fibers and cell migration through the inhibition of RhoA activity, which is controlled by binding of Kank to 14-3-3 in PI3K–Akt signaling.

14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion

“…Other 14-3-3 family members were shown previously to regulate intermediate filament architecture by functioning as K8/K18 solubility cofactors in a PKCζ-dependent mechanism (40)(41)(42). In addition, a number of studies have highlighted different mechanisms by which 14-3-3 family members regulate actin dynamics either through stabilizing cofilin phosphorylation or by inhibiting signals through the AKT-RhoA pathway (12,(43)(44)(45).…”

Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration

“…40 This stimulates the formation of actin stress fibers through the activation of RhoA. 41 Therefore, PI3K signaling evoked by truncated Tie2 ( Figure 5) may be involved in the formation of actin stress fibers in endothelial cells ( Figure 6A), leading to endothelial cell retraction. Third, when epithinexpressing cells escape the vasculature, the matrix-degrading activity of epithin 19 can generate a pathway for the cells to invade further into the layers of the extracellular matrix.…”

Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions

“…Recently, we found that liprin-b1 interacts with KANK1 (van der Vaart et al, 2013), one of the four members of the KANK family of proteins, which were proposed to act as tumor suppressors and regulators of cell polarity and migration through Rho GTPase signaling (Gee et al, 2015;Kakinuma et al, 2008Li et al, 2011;Roy et al, 2009). KANK1 recruits the kinesin-4 KIF21A to CMSCs, which inhibits microtubule polymerization and prevents microtubule overgrowth at the cell edge van der Vaart et al, 2013).…”