Abstract 44: EGFR and Dock180 activate MLK3 to drive invasion of glioblastoma cells

Glioblastoma (GBM) is the most common and deadly form of brain tumor in adults, with an average post-diagnosis survival time of 15 months. While GBMs rarely metastasize to distant organs, they readily invade into surrounding brain tissue, leading to incomplete surgical resection and subsequent tumor recurrence. Epidermal Growth Factor Receptor (EGFR) signaling is aberrantly activated in a majority of GBM tumors, and is clearly implicated in multiple malignant phenotypes, including migration and invasion. However, direct targeting of EGFR has been largely unsuccessful, for multiple reasons, including compensatory upregulation of other RTKs. Thus, identifying and targeting key signaling nodes that are downstream of multiple RTKs is of therapeutic importance. Several guanine nucleotide exchange factors (GEFs), including Dock180, a Rac1 GEF, are implicated in GBM invasion through activation of small GTPases, Rac and Cdc42. The Mixed Lineage Kinases (MLKs) are a family of cytosolic MAP3Ks that activate multiple MAPK pathways, including the c-Jun N-terminal kinase (JNK), ERK, and p38 pathways. MLK3 is activated through the binding of activated, GTP-bound Rac and/or Cdc42 to induce dimerization and activation. Herein, the role of MLK signaling on GBM cell migration is investigated using an ATP-competitive pan-MLK inhibitor (previously in phase II/III clinical trials for Parkinson's disease), as well as siRNA targeting MLK3. Data from this study demonstrate that both MLK inhibition a...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research