Abstract
Rac1 GTPase is hyperactivated in tumors and contributes to malignancy. Rac1 disruption of junctions requires its effector PAK1, but the precise mechanisms are unknown. Here, we show that E-cadherin is internalized via micropinocytosis in a PAK1-dependent manner without catenin dissociation and degradation. In addition to internalization, PAK1 regulates E-cadherin transport by fine-tuning Rab small GTPase function. PAK1 phosphorylates a core Rab regulator, RabGDIβ, but not RabGDIα. Phosphorylated RabGDIβ preferentially associates with Rab5 and Rab11, which is predicted to promote Rab retrieval from membranes. Consistent with this hypothesis, Rab11 is activated by Rac1, and inhibition of Rab11 function partially rescues E-cadherin destabilization. Thus, Rac1 activation reduces surface cadherin levels as a net result of higher bulk flow of membrane uptake that counteracts Rab11-dependent E-cadherin delivery to junctions (recycling and/or exocytosis). This unique small GTPase crosstalk has an impact on Rac1 and PAK1 regulation of membrane remodeling during epithelial dedifferentiation, adhesion, and motility.
Highlights
The small GTPase Rac1 plays a key role in the regulation of cell–cell adhesion and epithelial function in health and disease
Keratinocytes expressing activated Rac1—constitutively active Q61L mutation, similar to the activating Q61L and G12V mutations found in oncogenic Ras—had junctions disrupted in a characteristic pattern: E-cadherin receptors were removed from the cell corners first (Fig. 1 A, arrows; Braga et al, 2000)
To understand the mechanism by which Rac1 promotes E-cadherin internalization, we initially assessed whether catenins were selectively released from internalized cadherin complexes
Summary
The small GTPase Rac plays a key role in the regulation of cell–cell adhesion and epithelial function in health and disease. In a cancer context, uncontrolled Rac activation often correlates with metastatic behavior and poor prognosis, with cell–cell contact disruption, cell detachment, and enhanced migration (Porter et al, 2016). Destabilization of cadherin-dependent junctions by PAK1 activation is consistent with the role of other PAK family members in the adhesion of tumor cell lines (Fram et al, 2014; Ismail et al, 2017; Morse et al, 2016; Selamat et al, 2015) and the wellestablished PAK1 function in promoting tumor migration and metastasis (Kumar and Li, 2016)
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