PAK is required for the disruption of E-cadherin adhesion by the small GTPase Rac

被引:43
作者
Lozano, Encarnacion [1 ,2 ]
Frasa, Marieke A. M. [1 ]
Smolarczyk, Katarzyna [1 ]
Knaus, Ulla G. [3 ]
Braga, Vania M. M. [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Fac Med, Mol Med Sect, NHLI, London SW7 2AZ, England
[2] Univ London Imperial Coll Sci Technol & Med, Fac Life Sci, Ecol & Evolut Res Sect, London SW7 2AZ, England
[3] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
基金
英国医学研究理事会;
关键词
Rac small GTPase; E-cadherin; PAK; cell-cell adhesion; Keratinocytes;
D O I
10.1242/jcs.016121
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
E-cadherin cell-cell adhesion plays a major role in the maintenance of the morphology and function of epithelial tissues. Modulation of E-cadherin function is an important process in morphogenesis and tumour de-differentiation. We have previously shown that constitutively active Rac1 induces the disassembly of E-cadherin complexes from junctions in human keratinocytes. Here, we compare this activity in three members of the Rac subfamily ( Rac1, Rac3 and Rac1b) and investigate the molecular mechanisms underlying Rac1-induced destabilization of junctions. We demonstrate that Rac3 shares with Rac1 the ability to interfere with cadherin-mediated adhesion. Rac1b is an alternative splice variant of Rac1 but, surprisingly, Rac1b cannot induce junction disassembly. Thus, Rac family members differ on their potential to perturb keratinocyte cell-cell contacts. The mechanism through which Rac promotes disassembly of cadherin-dependent adhesion does not involve an increase in contractility. Instead, activation of the Rac target PAK1 is necessary for destabilization of cell-cell contacts. Inhibition of PAK1 by dominant-negative constructs or depletion of endogenous PAK1 by RNA interference efficiently blocked Rac1-induced perturbation of junctions. Interestingly, PAK1 cannot be activated by Rac1b, suggesting that this may contribute to the inability of Rac1b to disrupt cell-cell contacts in keratinocytes. As PAK1 also plays a crucial role in lamellipodia formation, our data indicate that PAK1 is at the interface between junction destabilization and increased motility during morphogenetic events.
引用
收藏
页码:933 / 938
页数:6
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