%0 Journal Article
%T A Novel Interaction between Pyk2 and MAP4K4 Is Integrated with Glioma Cell Migration
%A Joseph C. Loftus
%A Zhongbo Yang
%A Jean Kloss
%A Harshil Dhruv
%A Nhan L. Tran
%A Daniel L. Riggs
%J Journal of Signal Transduction
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/956580
%X Glioma cell migration correlates with Pyk2 activity, but the intrinsic mechanism that regulates the activity of Pyk2 is not fully understood. Previous studies have supported a role for the N-terminal FERM domain in the regulation of Pyk2 activity as mutations in the FERM domain inhibit Pyk2 phosphorylation. To search for novel protein-protein interactions mediated by the Pyk2 FERM domain, we utilized a yeast two-hybrid genetic selection to identify the mammalian Ste20 homolog MAP4K4 as a binding partner for the Pyk2 FERM domain. MAP4K4 coimmunoprecipitated with Pyk2 and was a substrate for Pyk2 but did not coimmunoprecipitate with the closely related focal adhesion kinase FAK. Knockdown of MAP4K4 expression inhibited glioma cell migration and effectively blocked Pyk2 stimulation of glioma cell. Increased expression of MAP4K4 stimulated glioma cell migration; however, this stimulation was blocked by knockdown of Pyk2 expression. These data support that the interaction of MAP4K4 and Pyk2 is integrated with glioma cell migration and suggest that inhibition of this interaction may represent a potential therapeutic strategy to limit glioblastoma tumor dispersion. 1. Introduction Glioblastoma multiforme (GBM) is the most common form of all primary adult brain tumors. Although significant technical advances in surgical and radiation treatments for brain tumors have emerged, their impact on clinical outcome for patients has been modest [1, 2]. Of the features that characterize GBM, arguably none is more clinically significant than the propensity of glioma cells to aggressively invade the surrounding normal brain tissue [3]. These invasive cells render complete resection impossible, confer strong resistance to chemo- and radiation therapy, and virtually assure the rise of secondary tumors that develop at the resection margins that drive further invasion [4]. Meaningful advances in clinical outcomes will require identification and targeting of key signaling effectors mediating glioma invasion. The nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) serves as a point of integration for signaling from cell surface receptors including integrin adhesion receptors, G-protein coupled receptors, and receptor tyrosine kinases [5¨C7]. As such, signaling from Pyk2 has been implicated in a variety of cellular processes including migration, cell survival, and proliferation. We have demonstrated in glioblastoma tumor samples that Pyk2 expression is upregulated in invasive glioma cells relative to cells in their cognate tumor cores [8] and that increased Pyk2
%U http://www.hindawi.com/journals/jst/2013/956580/