Regulation of Cell Migration by WNK1

Cell motility is an immensely complex process that involves reorganization of the cytoskeleton, and consequent membrane deformation, triggered by a variety of motogenic stimuli, including growth and chemotactic factors, hormones, and elements of the extracellular matrix. My graduate research has focused on the regulation of cell motility by a serine/threonine protein kinase, WNK1 (With No lysine (K)1), so named because of the absence of a conserved lysine within the catalytic domain. Although WNK1 has been most thoroughly characterized for its role in controlling ion flux in the kidney, emerging evidence points to its essential participation in both intracellular membrane trafficking and overall cell movement. Having confirmed a previous observation that depletion of WNK1 in cultured cells interferes with wound closure in an established motility assay, I next sought to identify specific aspects of cytoskeleton remodeling that are impaired by reduction of WNK1 expression. The most dramatic effect of siRNA-mediated WNK1 depletion was an increase in the proportion of polymerized (F) actin. Surprisingly, this redistribution was accompanied by a corresponding increase in the proportion of active, unphosphorylated cofilin, an F-actin depolymerizing factor, most likely reflecting engagement of a feedback homeostatic mechanism. To understand the pathway(s) whereby WNK1 regulates stimulus-dependent actin dynamics, I examined three potential pathways known to impact cell motility: 1. Remodeling of subcellular cytoskeletal structures, including circular dorsal ruffles and stress fibers; 2. Activation of downstream effectors of phosphatidylinositol 3-kinase (PI3K), including Akt and LIMK1; 3. Regulation of proteins that control the cytoskeletal re-organization including the ERM proteins (Ezrin, Moesin, and Radixin), cofilin, and the Rho family of GTPases, including RhoA and Rac1.

Author dc:creator

• Estrada, Armando, III 1980-

Contributors dc:contributor

• Taussig, Ronald
• Albanesi, Joseph P.
• Cobb, Melanie H.
• Huang, Chou-Long

• Cell Movement
• Cytoskeleton
• Protein-Serine-Threonine Kinases

Language dc:language

en

Identifier

https://hdl.handle.net/2152.5/1475
900282368

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/1475