Abstract
Repair of airway epithelium after injury requires migration of neighboring epithelial cells to injured areas. However, the molecular mechanisms regulating airway epithelial cell migration is not well defined. We have previously shown that XB130, a scaffold protein, is required for airway epithelial repair and regeneration in vivo, and interaction between XB130 and another scaffold protein, Tks5, regulates cell proliferation and survival in human bronchial epithelial cells. The objective of the present study was to determine the role of XB130 and Tks5 interaction in airway epithelial cell migration. Interestingly, we found that XB130 only promotes lateral cell migration, whereas, Tks5 promotes cell migration/invasion via proteolysis of extracellular matrix. Upon stimulation with EGF, PKC activator phorbol 12, 13-dibutyrate or a nicotinic acetylcholine receptor ligand, XB130 and Tks5 translocated to the cell membrane in a stimulus-dependent manner. The translocation and distribution of XB130 is similar to lamellipodial marker, WAVE2; whereas Tks5 is similar to podosome marker, N-WASP. Over-expression of XB130 or Tks5 alone enhances cell migration, whereas co-expression of both XB130 and Tks5 inhibits cell migration processes and signaling. Furthermore, XB130 interacts with Rac1 whereas Tks5 interacts with Cdc42 to promote Rho GTPase activity. Our results suggest that dissociation between XB130 and Tks5 may facilitate lateral cell migration via XB130/Rac1, and vertical cell migration via Tks5/Cdc42. These molecular mechanisms will help our understanding of airway epithelial repair and regeneration.
Highlights
The airway epithelium is the first line of defense in response to various chemical, physical and inflammatory insults, and depending on the severity of injury, endures surface epithelium permeability, cell death and denudation of the epithelial cell lining [1]
We recently showed that XB130 interacts with another scaffold protein, tyrosine kinase substrate with five Src homology 3 (SH3) domains (Tks5) [16]
Tks5 has been shown to be involved in cytoskeletal remodeling for the formation of podosomes that secrete proteolytic enzymes for the degradation of the extracellular matrix (ECM) [18]
Summary
The airway epithelium is the first line of defense in response to various chemical, physical and inflammatory insults, and depending on the severity of injury, endures surface epithelium permeability, cell death and denudation of the epithelial cell lining [1]. Airway epithelial cell migration is an early event for repair and regeneration of epithelium after injury [1]. Our current understanding of the molecular processes that regulate airway epithelial cell migration is limited. Scaffold proteins are critical for coordinating the interactions and transport of proteins, a key role that couples signal transduction events www.impactjournals.com/oncotarget to regulated cell function [3]. Several scaffold proteins have been implicated in the regulation of cell migration, such as the growth factor receptor-bound protein (Grb) family, tyrosine kinase substrate (Tks) family and noncatalytic region of tyrosine kinase adaptor protein (Nck) family [4,5,6]. XB130 is a scaffold protein that belongs to the actin filament associated protein family and acts as a signal transduction molecule to mediate cell growth, survival and cytoskeleton remodeling [7]
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